Substituted Triazolo-Pyrazine Compounds

ABSTRACT

The present invention relates to substituted triazolo-pyrazine compounds and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing substituted triazolo-pyrazine compounds and methods of treating cell proliferative disorders, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Provisional Application No. 61/290,909, filed Dec. 30, 2009, and U.S.Provisional Application No. 61/362,124, filed Jul. 7, 2010, the contentsof each of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of death in the United States,exceeded only by heart disease. (Cancer Facts and Figures 2004, AmericanCancer Society, Inc.). Despite recent advances in cancer diagnosis andtreatment, surgery and radiotherapy may be curative if a cancer is foundearly, but current drug therapies for metastatic disease are mostlypalliative and seldom offer a long-term cure. Even with newchemotherapies entering the market, the need continues for new drugseffective in monotherapy or in combination with existing agents as firstline therapy, and as second and third line therapies in treatment ofresistant tumors.

Cancer cells are by definition heterogeneous. For example, within asingle tissue or cell type, multiple mutational “mechanisms” may lead tothe development of cancer. As such, heterogeneity frequently existsbetween cancer cells taken from tumors of the same tissue and same typethat have originated in different individuals. Frequently observedmutational “mechanisms” associated with some cancers may differ betweenone tissue type and another (e.g., frequently observed mutational“mechanisms” leading to colon cancer may differ from frequently observed“mechanisms” leading to leukemias). It is therefore often difficult topredict whether a particular cancer will respond to a particularchemotherapeutic agent (Cancer Medicine, 5^(th) edition, Bast et al., B.C. Decker Inc., Hamilton, Ontario).

Components of cellular signal transduction pathways that regulate thegrowth and differentiation of normal cells can, when dysregulated, leadto the development of cellular proliferative disorders and cancer.Mutations in cellular signaling proteins may cause such proteins tobecome expressed or activated at inappropriate levels or atinappropriate times during the cell cycle, which in turn may lead touncontrolled cellular growth or changes in cell-cell attachmentproperties. For example, dysregulation of receptor tyrosine kinases bymutation, gene rearrangement, gene amplification, and overexpression ofboth receptor and ligand has been implicated in the development andprogression of human cancers.

FGFR2 is a member of the fibroblast growth factor receptor family, whereamino acid sequence is highly conserved between members and throughoutevolution. FGFR family members differ from one another in their ligandaffinities and tissue distribution. A full-length representative proteinconsists of an extracellular region, composed of threeimmunoglobulin-like domains, a single hydrophobic membrane-spanningsegment and a cytoplasmic tyrosine kinase domain. The extracellularportion of the protein interacts with fibroblast growth factors, settingdownstream signals, ultimately influencing mitogenesis anddifferentiation.

Alterations in the activity (expression) of the FGFR2 gene areassociated with certain cancers. The altered gene expression may enhanceseveral cancer-related events such as cell proliferation, cell movement,and the development of new blood vessels that nourish a growing tumor.The FGFR2 gene is abnormally active (overexpressed) in certain types ofstomach cancers, and this amplification is associated with a pooreroutcome. Abnormal expression of FGFR2 is also found in patients withprostate cancer. More than 60 percent of women with breast cancer, inthe United States, carry at least a single mutation in this gene aswell.

Accordingly, new compounds and methods for modulating FGFR2 genes andtreating proliferation disorders, including cancer, are needed. Thepresent invention addresses these needs.

SUMMARY OF THE INVENTION

The present invention provides, in part, substituted triazolo-pyrazinecompounds of formula I, II or III and methods of preparing the compoundsof formula I, II or III:

or a pharmaceutically acceptable salt or ester thereof, wherein:

R₁ is H, unsubstituted or substituted C₁-C₆ alkyl or Q₁-T₁;

R₂ is H, unsubstituted or substituted C₁-C₆ alkyl or Q₂-T₂; or R₁ andR₂, together with the atom they attach to, form an unsubstituted orsubstituted heteroaryl or heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S;

R₃ is H, unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆,C(O)R₅ or S(O)₂R₅;

R₄ is H or unsubstituted or substituted C₁-C₆ alkyl;

R₅ and R₆ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

n is 0, 1 or 2;

each R_(p) is independently OH, halogen, nitro, cyano or unsubstitutedC₁-C₆ alkyl;

Q₁ and Q₂ are each independently a bond or unsubstituted or substitutedC₁-C₆ alkyl linker;

T₁ and T₂ are each independently unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S;

m is 0, 1, 2, 3, 4 or 5;

each R_(q) is independently OH, halogen, nitro, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₆-C₁₀ aryloxy, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

o is 0, 1, 2, 3, 4 or 5; and

each R_(r) is independently OH, halogen, nitro, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₆-C₁₀ aryloxy, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S; or any two adjacent R_(r), together with the carbon atoms theyattach to, form a 5- or 6-member ring which optionally comprises 1-4heteroatoms selected from N, O and S and optionally is substituted.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of each of the formulae describedherein and one or more pharmaceutically acceptable carriers.

The present invention also provides enantiomers of the formulaedescribed herein.

The present invention also provides methods of treating a cellproliferative disorder by administering to a subject in need thereof, atherapeutically effective amount of a compound of each of the formulaedescribed herein, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof, in combination with apharmaceutically acceptable carrier, such that the disorder is treated.

The present invention also provides methods of treating cancer byadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of each of the formulae described herein, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, in combination with a pharmaceutically acceptablecarrier, such that the cancer is treated.

The present invention also provides methods of selectively inducing celldeath in precancerous or cancerous cells by contacting a cell with aneffective amount of a compound of each of the formulae described herein,or a pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, in combination with a pharmaceutically acceptablecarrier, such that contacting the cell results in selective induction ofcell death in the precancerous or cancer cells.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION 1. SUBSTITUTED TRIAZOLO-PYRAZINECOMPOUNDS

The present invention provides novel substituted triazolo-pyrazinecompounds, synthetic methods for making the compounds, pharmaceuticalcompositions containing them and various uses of the disclosedcompounds.

The present invention provides the compounds of formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein:

R₁ is H, unsubstituted or substituted C₁-C₆ alkyl or Q₁-T₁;

R₂ is H, unsubstituted or substituted C₁-C₆ alkyl or Q₂-T₂; or R₁ andR₂, together with the atom they attach to, form an unsubstituted orsubstituted heteroaryl or heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S;

R₃ is H, unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆,C(O)R₅ or S(O)₂R₅;

R₄ is H or unsubstituted or substituted C₁-C₆ alkyl;

R₅ and R₆ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

n is 0, 1 or 2;

each R_(p) is independently OH, halogen, nitro, cyano or unsubstitutedC₁-C₆ alkyl;

Q₁ and Q₂ are each independently a bond or unsubstituted or substitutedC₁-C₆ alkyl linker; and

T₁ and T₂ are each independently unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, n is 0.

For example, n is 1 or 2.

For example, each R_(p) is independently unsubstituted, C₁-C₆ straightchain or C₃-C₆ branched alkyl, including but not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl.

For example, one of R₁ and R₂ is H.

For example, R₂ is H and R₁ is unsubstituted or substituted, C₁-C₆straight chain or C₃-C₆ branched alkyl, including but not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,s-pentyl and n-hexyl, each of which is optionally substituted.

For example, R₂ is H and R₁ is Q₁-T₁.

For example, R₂ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted and R₁ is unsubstitutedor substituted, C₁-C₆ straight chain or C₃-C₆ branched alkyl, includingbut not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl and n-hexyl, each of which is optionallysubstituted.

For example, R₂ is methyl, ethyl or n-propyl and R₁ is methyl, ethyl orn-propyl.

For example, R₂ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted and R₁ is Q₁-T₁.

For example, R₂ is methyl, ethyl, n-propyl or n-butyl and R₁ is Q₁-T₁.

For example, R₁ is Q₁-T₁ and R₂ is Q₂-T₂.

For example, Q₁ is a bond.

For example, Q₁ is an unsubstituted or substituted, C₁-C₆ straight chainor C₃-C₆ branched alkyl linker, including but not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl linker.

For example, Q₁ is a methyl, ethyl or propyl linker.

For example, T₁ is unsubstituted phenyl.

For example, T₁ is phenyl substituted with one or more groups, each ofwhich is independently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted C₆-C₁₀ aryloxy (e.g., phenoxy),

g) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

h) unsubstituted or substituted C₃-C₁₀ carbocycle, and

i) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₁ is phenyl substituted with one, two, three or moregroups selected from hydroxyl, fluorine, chlorine, bromine, iodine,methyl, ethyl, propyl, i-propyl, t-butyl, trifluoromethyl, methoxy,cyano, nitro, dimethylamino, phenyl and phenoxy.

For example, T₁ is unsubstituted naphthyl.

For example, T₁ is naphthyl substituted with one or more groups, each ofwhich is independently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), and di-C₁-C₆ alkylamino (e.g.,dimethylamino, diethylamino, dipropylamino, dibutylamino anddipentylamino).

For example, T₁ is indenyl or dihydroindenyl, and is optionallysubstituted.

For example, T₁ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted with one ormore groups, each of which is independently selected from the groupconsisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₁ is pyridinyl, indolyl or benzoimidazolyl, each of whichis optionally substituted with one or more groups selected from methyl,ethyl, methoxy, ethoxy, fluorine, chlorine, bromine and iodine.

For example, T₁ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, T₁ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyl,morpholinyl, dihydrobenzodioxinyl and dihydrobenzofuranyl, and the like,and is optionally substituted with one or more groups, each of which isindependently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₁ is pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyland 3-pyrrolidinyl) or piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl,3-piperidinyl and 4-piperidinyl), each of which is optionallysubstituted.

For example, Q₂ is a bond.

For example, Q₂ is an unsubstituted or substituted, C₁-C₆ straight chainor C₃-C₆ branched alkyl linker, including but not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl linker.

For example, Q₂ is a methyl, ethyl or propyl linker.

For example, T₂ is unsubstituted phenyl.

For example, T₂ is phenyl substituted with one or more groups, each ofwhich is independently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano, b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted C₆-C₁₀ aryloxy (e.g., phenoxy),

g) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

h) unsubstituted or substituted C₃-C₁₀ carbocycle, and

i) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₂ is phenyl substituted with one, two, three or moregroups selected from hydroxyl, fluorine, chlorine, bromine, iodine,methyl, ethyl, propyl, i-propyl, t-butyl, trifluoromethyl and methoxy.

For example, T₂ is naphthyl, indenyl or dihydroindenyl, and isoptionally substituted.

For example, T₂ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted with one ormore groups, each of which is independently selected from the groupconsisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₂ is pyridinyl and is optionally substituted.

For example, T₂ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, T₂ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted with one ormore groups, each of which is independently selected from the groupconsisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, R₁ is Q₁-T₁ and R₂ is unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted phenyl or unsubstituted orsubstituted pyridinyl.

For example, R₁ and R₂, together with the atom they attach to, form aheteroaryl or heterocycle selected from pyrrolyl, furanyl, thiophene,thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, dihydroquinolinyl,naphthrydinyl, indolyl, purinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyl andmorpholinyl, and is optionally substituted with one or more groups, eachof which is independently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, R₁ and R₂, together with the atom they attach to, form aheteroaryl or heterocycle and is substituted with one or more groupsselected from methyl, ethyl, trifluoromethyl, methoxy, fluorine,chlorine, bromine, iodine and oxodihydrobenzoimidazolyl.

For example, R₁ and R₂, together with the atom they attach to, form apiperidinyl or dihydroquinolinyl, each of which is optionallysubstituted with benzoimidazolonyl.

For example, R₃ is H.

For example, R₃ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₃ is C(O)OR₅, C(O)NR₅R₆, C(O)R₅ or S(O)₂R₅.

For example, R₃ is C(O)OR₅.

For example, R₅ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₅ is isopropyl.

For example, R₅ is phenyl or naphthyl, and is optionally substituted.

For example, R₅ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₅ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₅ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, R₆ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₆ is phenyl or naphthyl, and is optionally substituted.

For example, R₆ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₆ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₆ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, R₄ is H.

For example, R₄ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, the present invention provides compounds having thefollowing formula:

wherein R₁ and R₂ are defined according to formula I.

The present invention provides the compounds of formula II:

or a pharmaceutically acceptable salt or ester thereof, wherein:

R₂ is H, unsubstituted or substituted C₁-C₆ alkyl or Q₂-T₂;

R₃ is H, unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆,C(O)R₅ or S(O)₂R₅;

R₅ and R₆ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

Q₁ and Q₂ are each independently a bond or unsubstituted or substitutedC₁-C₆ alkyl linker;

T₂ is unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

m is 0, 1, 2, 3, 4 or 5; and

each R_(q) is independently OH, halogen, nitro, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₆-C₁₀ aryloxy, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S.

For example, Q₁ is a bond.

For example, Q₁ is an unsubstituted or substituted, C₁-C₆ straight chainor C₃-C₆ branched alkyl linker, including but not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl linker.

For example, Q₁ is a methyl, ethyl or propyl linker.

For example, the present invention provides compounds having thefollowing formula:

For example, m is 0.

For example, m is 1 or 2.

For example, each R_(q) is independently fluorine, chlorine, bromine oriodine.

For example, each R_(q) is independently unsubstituted or substituted,C₁-C₆ straight chain or C₃-C₆ branched alkyl, including but not limitedto, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl,n-pentyl, s-pentyl and n-hexyl, each of which is optionally substitutedwith hydroxyl or halogen (e.g., fluorine, chlorine, bromine and iodine).

For example, each R_(q) is independently unsubstituted or substituted,C₁-C₆ straight chain or C₃-C₆ branched alkyl and is perhalogenated(e.g., trifluoromethyl).

For example, each R_(q) is independently unsubstituted or substitutedC₁-C₆ alkoxy, including but not limited to, methoxy, ethoxy, propyloxy,i-propyloxy, butoxy, t-butoxy, methylenedioxy and ethylenedioxy, each ofwhich is optionally substituted with halogen (e.g., fluorine, chlorine,bromine and iodine)).

For example, each R_(q) is independently unsubstituted or substitutedC₁-C₆ alkoxy and is perhalogenated (e.g., trifluoromethoxy).

For example, each R_(q) is independently amino, C₁-C₆ alkylamino (e.g.,methylamino, ethylamino, propylamino, butylamino and pentylamino),di-C₁-C₆ alkylamino (e.g., dimethylamino, diethylamino, dipropylamino,dibutylamino and dipentylamino).

For example, each R_(q) is independently unsubstituted or substitutedC₆-C₁₀ aryl (e.g., phenyl and naphthyl).

For example, each R_(q) is independently unsubstituted or substitutedC₆-C₁₀ aryloxy (e.g., phenoxy).

For example, each R_(q) is independently unsubstituted or substitutedheteroaryl selected from pyrrolyl, furanyl, thiophene, thiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, each R_(q) is independently unsubstituted or substitutedcarbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, and is optionally substituted.

For example, each R_(q) is independently heterocycle selected frompyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl,piperidinone, piperazinyl and morpholinyl, and the like, and isoptionally substituted.

For example, each R_(q) is independently hydroxyl, fluorine, chlorine,bromine, iodine, methyl, ethyl, propyl, i-propyl, t-butyl,trifluoromethyl, methoxy, cyano, nitro, methylamino, ethylamino,dimethylamino, diethylamino, phenyl and phenoxy.

For example, R₂ is H.

For example, R₂ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₂ is methyl, ethyl, n-propyl or n-butyl.

For example, R₂ is Q₂-T₂.

For example, Q₂ is a bond.

For example, Q₂ is an unsubstituted or substituted, C₁-C₆ straight chainor C₃-C₆ branched alkyl linker, including but not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyland n-hexyl linker.

For example, Q₂ is a methyl, ethyl or propyl linker.

For example, T₂ is unsubstituted phenyl.

For example, T₂ is phenyl substituted with one or more groups, each ofwhich is independently selected from the group consisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₂ is phenyl substituted with one, two, three or moregroups selected from hydroxyl, fluorine, chlorine, bromine, iodine,methyl, ethyl, propyl, i-propyl, t-butyl, trifluoromethyl and methoxy.

For example, T₂ is naphthyl, indenyl or dihydroindenyl, and isoptionally substituted.

For example, T₂ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted with one ormore groups, each of which is independently selected from the groupconsisting of:

a) hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino), di-C₁-C₆ alkylamino (e.g., dimethylamino,diethylamino, dipropylamino, dibutylamino and dipentylamino),

e) unsubstituted or substituted C₆-C₁₀ aryl (e.g., phenyl and naphthyl),

f) unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,

g) unsubstituted or substituted C₃-C₁₀ carbocycle, and

h) unsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, T₂ is pyridinyl and is optionally substituted.

For example, T₂ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, T₂ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, R₃ is H.

For example, R₃ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₃ is C(O)OR₅, C(O)NR₅R₆, C(O)R₅ or S(O)₂R₅.

For example, R₃ is C(O)OR₅.

For example, R₅ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₅ is isopropyl.

For example, R₅ is phenyl or naphthyl, and is optionally substituted.

For example, R₅ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₅ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₅ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, R₆ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₆ is phenyl or naphthyl, and is optionally substituted.

For example, R₆ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₆ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₆ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

The present invention provides the compounds of formula III:

or a pharmaceutically acceptable salt or ester thereof, wherein:

R₃ is H, unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆,C(O)R₅ or S(O)₂R₅;

R₅ and R₆ are each independently H, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S;

o is 0, 1, 2, 3, 4 or 5; and

each R_(r) is independently OH, halogen, nitro, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₆-C₁₀ aryloxy, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S; or any two adjacent R_(r), together with the carbon atoms theyattach to, form a 5- or 6-member ring which optionally comprises 1-4heteroatoms selected from N, O and S and optionally is substituted.

For example, R₃ is H.

For example, R₃ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₃ is C(O)OR₅, C(O)NR₅R₆, C(O)R₅ or S(O)₂R₅.

For example, R₃ is C(O)OR₅.

For example, R₅ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₅ is isopropyl.

For example, R₅ is phenyl or naphthyl, and is optionally substituted.

For example, R₅ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₅ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₅ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, R₆ is unsubstituted or substituted, C₁-C₆ straight chain orC₃-C₆ branched alkyl, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted.

For example, R₆ is phenyl or naphthyl, and is optionally substituted.

For example, R₆ is heteroaryl selected from pyrrolyl, furanyl,thiophene, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthrydinyl, indolyland purinyl, and the like, and is optionally substituted.

For example, R₆ is carbocycle selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, and is optionally substituted.

For example, R₆ is heterocycle selected from pyrrolidinyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyland morpholinyl, and the like, and is optionally substituted.

For example, the present invention provides compounds having thefollowing formula:

wherein R_(r) and o are defined according to formula III.

For example, o is 0.

For example, o is 1 or 2.

For example, each R_(r) is independently fluorine, chlorine, bromine oriodine.

For example, each R_(r) is independently unsubstituted or substituted,C₁-C₆ straight chain or C₃-C₆ branched alkyl, including but not limitedto, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl,n-pentyl, s-pentyl and n-hexyl, each of which is optionally substitutedwith hydroxyl or halogen (e.g., fluorine, chlorine, bromine and iodine).

For example, each R_(r) is independently unsubstituted or substituted,C₁-C₆ straight chain or C₃-C₆ branched alkyl and is perhalogenated(e.g., trifluoromethyl).

For example, each R_(r) is independently unsubstituted or substitutedC₁-C₆ alkoxy, including but not limited to, methoxy, ethoxy, propyloxy,i-propyloxy, butoxy, t-butoxy, methylenedioxy and ethylenedioxy, each ofwhich is optionally substituted with halogen (e.g., fluorine, chlorine,bromine and iodine)).

For example, each R_(r) is independently unsubstituted or substitutedC₁-C₆ alkoxy and is perhalogenated (e.g., trifluoromethoxy).

For example, each R_(r) is independently amino, C₁-C₆ alkylamino (e.g.,methylamino, ethylamino, propylamino, butylamino and pentylamino),di-C₁-C₆ alkylamino (e.g., dimethylamino, diethylamino, dipropylamino,dibutylamino and dipentylamino).

For example, each R_(r) is independently unsubstituted or substitutedC₆-C₁₀ aryl (e.g., phenyl and naphthyl).

For example, each R_(r) is independently unsubstituted or substitutedC₆-C₁₀ aryloxy (e.g., phenoxy).

For example, each R_(r) is independently unsubstituted or substitutedheteroaryl selected from pyrrolyl, furanyl, thiophene, thiazolyl,isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzofuranyl, benzoxazolyl, benzodioxazolyl,benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzothiophene,oxodihydrobenzoimidolyl, methylenedioxyphenyl, quinolinyl,isoquinolinyl, naphthrydinyl, indolyl and purinyl, and the like, and isoptionally substituted.

For example, each R_(r) is independently unsubstituted or substitutedcarbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, and is optionally substituted.

For example, each R_(r) is independently heterocycle selected frompyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl,piperidinone, piperazinyl and morpholinyl, and the like, and isoptionally substituted.

For example, each R_(r) is independently hydroxyl, fluorine, chlorine,bromine, iodine, methyl, ethyl, propyl, i-propyl, t-butyl,trifluoromethyl, methoxy, cyano, nitro, methylamino, ethylamino,dimethylamino, diethylamino, phenyl and oxodihydrobenzoimidazolyl.

For example, any two adjacent R_(r), together with the carbon atoms theyattach to, form a ring selected from the group consisting of phenyl,pyrrolyl, furanyl, thiophene, thiazolyl, isothiazolyl, imidazolyl,triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl,tetrahyrofuranyl, piperidinyl, piperidinone, piperazinyl andmorpholinyl, and is optionally substituted.

For example, the present invention provides compounds having thefollowing formula:

wherein:

R_(p1), R_(p2), R_(p3) and R_(p4) are each independently

a) H, hydroxyl, halogen (e.g., fluorine, chlorine, bromine and iodine),nitro, cyano,

b) unsubstituted or substituted C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl andn-hexyl, each of which is optionally substituted with hydroxyl orhalogen (e.g., fluorine (e.g., the substituted alkyl is —CF₃ or —CHF₂),chlorine, bromine and iodine)),

c) unsubstituted or substituted C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propyloxy, i-propyloxy, butoxy, t-butoxy, methylenedioxy andethylenedioxy, each of which is optionally substituted with halogen(e.g., fluorine (e.g., the substituted alkoxy is —OCF₃), chlorine,bromine and iodine)),

d) amino, C₁-C₆ alkylamino (e.g., methylamino, ethylamino, propylamino,butylamino and pentylamino) and di-C₁-C₆ alkylamino (e.g.,dimethylamino, diethylamino, dipropylamino, dibutylamino anddipentylamino).

For example, one of R_(p1), R_(p2), R_(p3) and R_(p4) is H.

For example, two of R_(p1), R_(p2), R_(p3) and R_(p4) are H.

For example, three of R_(p1), R_(p2), R_(p3) and R_(p4) are H.

For example, R_(p1), R_(p2), R_(p3) and R_(p4) are each H.

For example, R_(p1), R_(p2), R_(p3) and R_(p4) are each independentlymethyl, ethyl, trifluoromethyl, methoxy and ethoxy.

Representative compounds of the present invention include compoundslisted in Table 1.

TABLE 1 Compound No. Structure Chemical Name 1

Isopropyl (8-((4-fluorophenyl) (methyl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 2

N⁸-(4-fluorophenyl)-N⁸-methyl- [1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 3

Isopropyl {8-[(4-chlorophenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 4

isopropyl {8-[(2-methoxy-6- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl)carbamate 5

isopropyl {8-[(3-methoxybenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 6

Isopropyl [8-(3,4-dihydroquinolin- 1(2H)-yl)[1,2,4]triazolo[4,3-a]pyrazin-3-yl]carbamate 7

isopropyl {8-[(5-chloro-2- methoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 8

Isopropyl {8-[benzyl(4-methylpyridin- 2-yl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 9

Isopropyl {8-[(4-chlorobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 10

Isopropyl {8-[(biphenyl-3- ylmethyl)amino][1,2,4]trizolo[4,3-a]pyrazin-3-yl}carbamate 11

Isopropyl {8-[(4-methoxyphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 12

Isopropyl {8-[butyl(phenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 13

isopropyl {8-[(2-chlorophenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 14

isopropyl {8-[(2-methylphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 15

isopropyl {8-[(2-methoxybenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 16

Isopropyl {8-[(2-chlorophenyl) (methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 17

isopropyl (8-{[4-(trifluoromethyl) benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 18

Isopropyl {8-[(4-ethylbenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 19

isopropyl {8-[(3-methylbenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 20

Isopropyl {8-[(3-piperidin-1- ylpropyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 21

Isopropyl (8-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}[1,2,4]triazolo[4,3-a] pyrazin-3-yl)carbamate 22

isopropyl {8-[(4-tert-butylbenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 23

isopropyl{ 8-[(2-methoxy-5- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 24

isopropyl {8-[(3-chlorobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 25

Isopropyl (8-{[4-(dimethylamino) phenyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 26

Isopropyl (8-{[2-(4- methylphenyl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 27

Isopropyl {8-[(2-chlorobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 28

isopropyl (8-{[2-(4-fluorophenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 29

Isopropyl {8-[(2-phenylethyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 30

isopropyl {8-[benzyl(methyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 31

isopropyl (8-{[2-(3,5-dimethoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 32

Isopropyl {8-[(2-chloro-5- methoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 33

Isopropyl (8-{[2-(3,4-dimethoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 34

isopropyl [8-(2,3-dihydro-1H-inden-5-ylamino)[1,2,4]triazolo[4,3-a]pyrazin- 3-yl]carbamate 35

isopropyl {8-[(2,4-dimethoxyphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 36

isopropyl (8-{[2-(4-phenoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 37

Isopropyl {8-[(4-methoxyphenyl) (methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 38

Isopropyl {8-[(2-chloro-6- fluorophenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 39

isopropyl {8-[(2-methoxyphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 40

Isopropyl {8-[methyl(3- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 41

isopropyl {8-[(2-methoxyphenyl) (methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 42

isopropyl (8-{[2-(3-methylphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 43

Isopropyl (8-anilino[1,2,4]triazolo [4,3-a]pyrazin-3-yl)carbamate 44

Isopropyl (8-{[2-(4-methoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 45

Isopropyl {8-[(4-methoxybenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 46

isopropyl {8-[(2,5-dimethoxyphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 47

Isopropyl {8-[(4-methylphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 48

isopropyl (8-{[2-(trifluoromethyl) benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 49

Isopropyl {8-[(3-chloro-4- methylbenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 50

isopropyl {8-[(4-tert-butylphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 51

Isopropyl {8-[(4-cyanophenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 52

isopropyl {8-[(4-bromophenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 53

Isopropyl {8-[methyl(pyridin-2- yl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 54

Isopropyl (8-{[2-(3-methoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 55

Isopropyl {8-[4-(2-oxo-2,3-dihydro- 1H-benzimidazol-1-yl)piperidin-1-yl][1,2,4]triazolo[4,3-a] pyrazin-3-yl}carbamate 56

isopropyl [8-(1H-benzimidazol-2- ylamino)[1,2,4]triazolo[4,3-a]pyrazin-3-yl]carbamate 57

Isopropyl {8-[(3,4-dimethoxybenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 58

isopropyl (8-{[2-(2-methoxyphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 59

isopropyl (8-piperidin-1-yl[1,2,4] triazolo[4,3-a]pyrazin-3-yl)carbamate60

Isopropyl {8-[(4-fluorophenyl) (methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 61

isopropyl {8-[(biphenyl-4- ylmethyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 62

isopropyl (8-{[2-(4-ethylphenyl) ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 63

isopropyl {8-[ethyl(2-methylphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 64

isopropyl {8-[ethyl(5-hydroxy-2- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 65

Isopropyl {8-[benzyl(4- methoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 66

isopropyl (8-{[3,5-bis (trifluoromethyl)benzyl]amino}[1,2,4]triazolo[4,3-a] pyrazin-3-yl)carbamate 67

isopropyl {8-[(3-chlorophenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 68

Isopropyl {8-[(4-bromobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 69

isopropyl {8-[methyl(4- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 70

Isopropyl {8-[methyl(propyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 71

Isopropyl {8-[(2,3-dimethylbenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 72

Isopropyl (8-(methyl(m-tolyl)amino)- [1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 73

Isopropyl {8-[(3,5-dimethylbenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 74

Isopropyl {8-[(2-chloro-5- methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 75

Isopropyl [8-(6-methoxy-3,4- dihydroquinolin-1(2H)-yl)[1,2,4]triazolo[4,3-a]pyrazin- 3-yl]carbamate 76

Isopropyl {8-[(3-pyrrolidin-1- ylpropyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 77

Isopropyl {8-[ethyl(1- naphthyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 78

Isopropyl {8-[(3-methylphenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 79

Isopropyl {8-[(pyridin-4- ylmethyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 80

isopropyl {8-[(2-bromobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 81

isopropyl (8-{[3-(trifluoromethyl) benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 82

isopropyl {8-[4-(5-chloro-2-oxo-2,3- dihydro-1H-benzimidazol-1-yl)piperidin-1-yl][1,2,4]triazolo[4,3- a]pyrazin-3-yl}carbamate 83

Isopropyl {8-[methyl(phenyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 84

isopropyl {8-[(2-fluorobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 85

isopropyl (8-{[2-(7-methyl-1H- indol-3-yl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 86

isopropyl {8-[(3-fluorobenzyl) amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 87

isopropyl {8-[(4-chlorophenyl) (methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 88

1-[1-(3-amino[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperidin-4-yl]-5-chloro- 1,3-dihydro-2H-benzimidazol-2-one89

N⁸-(2-methoxyphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 90

N⁸-[2-(4-methylphenyl)ethyl] [1,2,4]triazolo[4,3-a]pyrazine- 3,8-diamine91

N⁸-(4-methylbenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 92

N⁸-(2-bromobenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 93

N⁸-[2-(4-phenoxyphenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine94

N⁸-(4-fluorophenyl)-N-methyl [1,2,4]triazolo[4,3-a]pyrazine- 3,8-diamine95

N⁸-(4-methylphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 96

N⁸-(4-fluorobenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 97

N⁸-butyl-N⁸-phenyl[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 98

N⁸-[2-(2-fluorophenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine99

N⁸-(3-fluorophenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 100

N⁸-[4-(trifluoromethyl)benzyl][1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 101

N⁸-[2-(4-bromophenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine102

N⁸-(4-isopropylphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 103

N⁸-methyl-N⁸-(2-methylphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine104

N⁸-(biphenyl-4-ylmethyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 105

N⁸-(2,5-dimethoxyphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 106

N⁸-(5-chloro-2-methoxyphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine107

N⁸-methyl-N⁸-(4-methylphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine108

N⁸-(biphenyl-3-ylmethyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 109

N⁸-(4-bromophenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 110

N⁸-(4-chlorophenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 111

N⁸-(4-methoxybenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 112

N⁸-benzyl[1,2,4]triazolo[4,3-a] pyrazine-3,8-diamine 113

8-[7-(trifluoromethyl)-3,4-dihydro- quinolin-1(2H)-yl][1,2,4]triazolo[4,3-a]pyrazin-3-amine 114

N⁸-[2-(3-chlorophenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine115

N⁸-[2-(4-chlorophenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine116

N⁸-[4-(dimethylamino)phenyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine117

N⁸-[2-(4-methoxyphenyl)ethyl][1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine118

N⁸-(3-methylphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 119

N⁸-(4-chlorobenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 120

1-[1-(3-amino[1,2,4]triazolo[4,3-a] pyrazin-8-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one 121

N⁸-(2-fluorophenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 122

N⁸-benzyl-N⁸-(4-methoxyphenyl)[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 123

N⁸-(4-methoxyphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 124

N⁸-(2-methoxy-5-methylphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine125

N⁸-[2-(3,4-dimethoxyphenyl) ethyl][1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 126

N⁸-(1-naphthylmethyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 127

N⁸-(2-chloro-4-fluorophenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine128

N⁸-[3,5-bis(trifluoromethyl)benzyl][1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 129

N⁸-(4-chlorophenyl)-N⁸-methyl[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine130

8-(6-methyl-3,4-dihydroquinolin- 1(2H)-yl)[1,2,4]triazolo[4,3-a]pyrazin-3-amine 131

N⁸-(2,3-dimethylbenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 132

N⁸-(2-methoxybenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 133

N⁸-(3,4-dimethoxybenzyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine 134

N⁸-(4-tert-butylbenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 135

N⁸-[2-(3-methoxyphenyl)ethyl] [1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 136

N⁸-(2-phenylethyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 137

4-[(3-amino[1,2,4]triazolo[4,3-a] pyrazin-8-yl)(benzyl)amino]phenol 138

N⁸-(3-fluorophenyl)-N⁸-methyl[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine139

N⁸-(4-ethylbenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 140

N⁸-(4-bromobenzyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 141

N⁸-(2-chloro-4-methylphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine142

N⁸-(3-bromophenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 143

N⁸-[2-(trifluoromethyl)benzyl][1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 144

8-(6-methoxy-3,4-dihydroquinolin- 1(2H)-yl)[1,2,4]triazolo[4,3-a]pyrazin-3-amine 145

N⁸-(2,3-dihydro-1H-inden-5-yl)[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 146

N⁸-methyl-N⁸-phenyl[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 147

N⁸-(4-tert-butylphenyl)[1,2,4]triazolo [4,3-a]pyrazine-3,8-diamine 148

N⁸-[3-(trifluoromethyl)benzyl][1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 149

N⁸-(3,5-dimethylbenzyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine 150

3-[(3-amino[1,2,4]triazolo[4,3-a] pyrazin-8-yl)(ethyl)amino]-4-methylphenol 151

N⁸-(2-methoxyphenyl)-N⁸- methyl[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 152

N⁸-(4-methoxyphenyl)-N⁸- methyl[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 153

N⁸-(2-fluorobenzyl)[1,24]triazolo [4,3-a]pyrazine-3,8-diamine 154

N⁸-(2-chloro-5-methoxyphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine155

N⁸-(3-chlorophenyl)-N⁸-methyl[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine156

8-(3,4-dihydroquinolin-1(2H)- yl)[1,2,4]trizolo[4,3-a] pyrazin-3-amine157

N⁸-(2-methylphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine 158

N⁸-(3-chloro-4-methylbenzyl) [1,2,4]triazolo[4,3-a]pyrazine- 3,8-diamine159

N⁸-benzyl-N⁸-methyl[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine 160

N⁸-(2,5-dichlorophenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine 161

N⁸-(2,4-dimethoxyphenyl)[1,2,4] triazolo[4,3-a]pyrazine-3,8-diamine

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

“Heteroalkyl” groups are alkyl groups, as defined above, that have anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbon atoms.

As used herein, the term “cycloalkyl”, “C₃, C₄, C₅, C₆, C₇ or C₈cycloalkyl” or “C₃-C₈ cycloalkyl” is intended to include hydrocarbonrings having from three to eight carbon atoms in their ring structure.In one embodiment, a cycloalkyl group has five or six carbons in thering structure.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing one or more hydrogen atoms on one or more carbonsof the hydrocarbon backbone.

Such substituents can include, for example, alkyl, alkenyl, alkynyl,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “alkylaryl” or an “aralkyl” moiety is an alkylsubstituted with an aryl (e.g., phenylmethyl(benzyl)).

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, having from one to six, or inanother embodiment from one to four, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, two to six or of two to four carbon atoms.

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups andC₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. Forexample, C₁-C₆ alkyl linker is intended to include C₁, C₂, C₃, C₄, C₅and C₆ alkyl linker groups. Examples of alkyl linker include, moietieshaving from one to six carbon atoms, such as, but not limited to, methyl(—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—).

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includes straightchain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl,hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched alkenyl groups,cycloalkenyl (e.g., alicyclic) groups (e.g., cyclopropenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl oralkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenylsubstituted alkenyl groups. In certain embodiments, a straight chain orbranched alkenyl group has six or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from five to eight carbon atoms in theirring structure, and in one embodiment, cycloalkenyl groups have five orsix carbons in the ring structure. The term “C₂-C₆” includes alkenylgroups containing two to six carbon atoms. The term “C₃-C₆” includesalkenyl groups containing three to six carbon atoms.

“Heteroalkenyl” includes alkenyl groups, as defined herein, having anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbons.

The term “substituted alkenyl” refers to alkenyl moieties havingsubstituents replacing one or more hydrogen atoms on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic orheteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. In certainembodiments, a straight chain or branched alkynyl group has six or fewercarbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ forbranched chain). The term “C₂-C₆” includes alkynyl groups containing twoto six carbon atoms. The term “C₃-C₆” includes alkynyl groups containingthree to six carbon atoms.

“Heteroalkynyl” includes alkynyl groups, as defined herein, having anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbons.

The term “substituted alkynyl” refers to alkynyl moieties havingsubstituents replacing one or more hydrogen atoms on one or morehydrocarbon backbone carbon atoms. Such substituents can include, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Aryl” includes groups with aromaticity, including “conjugated”, ormulticyclic, systems with at least one aromatic ring. Examples includephenyl, benzyl, etc. Aryl also includes groups that are partiallyaromatic e.g., indene.

“Heteroaryl” groups are aryl groups, as defined above, having from oneto four heteroatoms in the ring structure, and may also be referred toas “aryl heterocycles” or “heteroaromatics”. As used herein, the term“heteroaryl” is intended to include a stable 5-, 6-, or 7-memberedmonocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromaticheterocyclic ring which consists of carbon atoms and one or moreheteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms,independently selected from the group consisting of nitrogen, oxygen andsulfur. The nitrogen atom may be substituted or unsubstituted (i.e., Nor NR wherein R is H or other substituents, as defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), where p=1 or 2). It is to be noted that total number of S andO atoms in the aromatic heterocycle is not more than 1. Heteroarylincludes groups that are partially aromatic e.g., e.g.,4-benzo[d]-imidazolone.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and thelike.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthridine, indole, benzofuran, purine, benzofuran, deazapurine,indolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). Examples of heterocycles include, but are not limitedto, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazineand tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted”, as used herein, means that any one or morehydrogen atmos on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R₁) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₁ moieties,then the group may optionally be substituted with up to two R₁ moietiesand R₁ at each occurrence is selected independently from the definitionof R₁. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo andiodo. The term “perhalogenated” generally refers to a moiety wherein allhydrogen atoms are replaced by halogen atoms.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom.Examples of moieties containing a carbonyl include, but are not limitedto, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides,etc.

“Acyl” includes moieties that contain the acyl radical (—C(O)—) or acarbonyl group. “Substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by, for example, alkyl groups,alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Aroyl” includes moieties with an aryl or heteroaromatic moiety bound toa carbonyl group. Examples of aroyl groups include phenylcarboxy,naphthyl carboxy, etc.

“Alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkylgroups, as described above, wherein oxygen, nitrogen or sulfur atomsreplace one or more hydrocarbon backbone carbon atoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups or alkoxyl radicals include, but are notlimited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxygroups. Examples of substituted alkoxy groups include halogenated alkoxygroups. The alkoxy groups can be substituted with groups such asalkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ether” or “alkoxy” includes compounds or moieties whichcontain an oxygen atom bonded to two carbon atoms or heteroatoms. Forexample, the term includes “alkoxyalkyl”, which refers to an alkyl,alkenyl, or alkynyl group covalently bonded to an oxygen atom which iscovalently bonded to an alkyl group.

The term “ester” includes compounds or moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc.

The term “thioalkyl” includes compounds or moieties which contain analkyl group connected with a sulfur atom. The thioalkyl groups can besubstituted with groups such as alkyl, alkenyl, alkynyl, halogen,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (includingalkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The term “thioether” includes moieties which contain a sulfur atombonded to two carbon atoms or heteroatoms. Examples of thioethersinclude, but are not limited to alkthioalkyls, alkthioalkenyls andalkthioalkynyls. The term “alkthioalkyls” include moieties with analkyl, alkenyl or alkynyl group bonded to a sulfur atom which is bondedto an alkyl group. Similarly, the term “alkthioalkenyls” refers tomoieties wherein an alkyl, alkenyl or alkynyl group is bonded to asulfur atom which is covalently bonded to an alkenyl group; andalkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynylgroup is bonded to a sulfur atom which is covalently bonded to analkynyl group.

As used herein, “amine” or “amino” includes moieties where a nitrogenatom is covalently bonded to at least one carbon or heteroatom.“Alkylamino” includes groups of compounds wherein nitrogen is bound toat least one alkyl group. Examples of alkylamino groups includebenzylamino, methylamino, ethylamino, phenethylamino, etc.“Dialkylamino” includes groups wherein the nitrogen atom is bound to atleast two additional alkyl groups. Examples of dialkylamino groupsinclude, but are not limited to, dimethylamino and diethylamino.“Arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively.“Alkylarylamino”, “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynylgroup bound to a nitrogen atom which is also bound to an alkyl group.“Acylamino” includes groups wherein nitrogen is bound to an acyl group.Examples of acylamino include, but are not limited to,alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term “amide” or “aminocarboxy” includes compounds or moieties thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl or alkynyl groups bound to an amino group whichis bound to the carbon of a carbonyl or thiocarbonyl group. It alsoincludes “arylaminocarboxy” groups that include aryl or heteroarylmoieties bound to an amino group that is bound to the carbon of acarbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”,“alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy”include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties,respectively, are bound to a nitrogen atom which is in turn bound to thecarbon of a carbonyl group. Amides can be substituted with substituentssuch as straight chain alkyl, branched alkyl, cycloalkyl, aryl,heteroaryl or heterocycle. Substituents on amide groups may be furthersubstituted.

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present invention. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the present inventioncan be converted to N-hydroxy or N-alkoxy compounds. For example,N-hydroxy compounds can be prepared by oxidation of the parent amine byan oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent invention includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formula. It is noted thatany crystal form, crystal form mixture, or anhydride or hydrate thereofis included in the scope of the present invention. Furthermore,so-called metabolite which is produced by degradation of the presentcompound in vivo is included in the scope of the present invention.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable minor images of each other aretermed “enantiomers” or sometimes optical isomers. A mixture containingequal amounts of individual enantiomeric forms of opposite chirality istermed a “racemic mixture”.

A carbon atom bonded to four nonidentical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisinvention include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-enamine.

It is to be understood that the compounds of the present invention maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present invention, and the naming ofthe compounds does not exclude any tautomer form.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have acommon core structure, and are substituted with various groups asdescribed herein. For example, all of the compounds represented byformula I are triazolo-pyrazine derivatives, and have formula I as acommon core.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres include,but are not limited to, acyl sulfonimides, tetrazoles, sulfonates andphosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176,1996.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

2. SYNTHESIS OF SUBSTITUTED TRIAZOLO-PYRAZINE COMPOUNDS

The present invention provides methods for the synthesis of thecompounds of each of the formulae described herein. The presentinvention also provides detailed methods for the synthesis of variousdisclosed compounds of the present invention according to the followingschemes as shown in the Examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups, therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester or prodrug thereof.

Compounds of the present invention can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentinvention.

Compounds of the present invention can be conveniently prepared by avariety of methods familiar to those skilled in the art. The compoundsof this invention with each of the formulae described herein may beprepared according to the following procedures from commerciallyavailable starting materials or starting materials which can be preparedusing literature procedures. These procedures show the preparation ofrepresentative compounds of this invention.

General Procedure

Steps 1-3 were carried out according to B. Koren, B. Stanovnik, M.Tisler, Monatshefte fuer Chemie, 83-90, 1988 and are described brieflybelow.

Step 1. Synthesis of 2-chloro-3-hydrazinylpyrazine hydrochloride

A solution of 2,3-dichloropyrazine (3.822 g, 25.65 mmol) in absoluteethanol (20 mL) was treated with hydrazine hydrate (2.74 mL) at roomtemperature. The mixture was stirred for 3 days then filtered and washedwith ethanol (20 mL) to yield 2-chloro-3-hydrazinylpyrazinehydrochloride as an off-white fluffy solid (4.04 g).

Step 2. Synthesis of ethyl2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate

A solution of 2-chloro-3-hydrazinylpyrazine hydrochloride (3.32 g, 18.34mmol) in anhydrous chloroform was treated with O-ethylcarbonisothiocyanatidate (1.9 mL, 16.11 mmol) at room temperature.Anhydrous methanol (10 mL) was added to the reaction mixture which wasthen concentrated under reduced pressure to yield ethyl2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (5.37 g) as anorange solid.

Step 3. Synthesis of ethyl8-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-ylcarbamate

A solution of bromine (653 μl, 12.74 mmol) in acetic acid (9 mL) wasadded to a solution of ethyl2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (3.523 g, 14.40mmol) in acetic acid (30 mL) at room temperature and stirred for afurther 80 minutes. The mixture was cooled in an ice-bath while 15%ammonium hydroxide solution (180 mL) was added to the reaction mixture,ensuring the reaction temperature remained below 30° C. The mixture wasdiluted with water (50 mL) and chloroform (120 mL) and filtered. Thecake was washed with chloroform (50 mL) and dried under high vacuum at50° C. to yield ethyl8-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-ylcarbamate (1.69 g) as a brownsolid.

Step 4. Synthesis ofisopropyl(8-((4-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate

A solution of8-chloro-[1,2,4]triazolo[4,3-f][1,2,4]triazin-3-ylcarbamate (49 mg, 0.2mmol) and 4-fluoro-N-methylaniline (25 mg, 0.2 mmol) in anhydrousisopropanol were heated to 100° C. for 24 hours. The solvent was removedunder reduced pressure to affordisopropyl(8-((4-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamatewhich could be purified by reverse phase column chromatography. LCMS:331 [M+H⁺].

Step 5. Synthesis ofN⁸-(4-fluorophenyl)-N⁸-methyl-[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine

The crude isopropyl(8-((4-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamatewas treated with 5N KOH aq (1 mL) and dioxane (2 mL). The mixture washeated to 125° C. for 48 hours then treated with 5N HCl (1 mL). Thesolvent was removed under reduced pressure to affordN8-(4-fluorophenyl)-N8-methyl-[1,2,4]triazolo[4,3-a]pyrazine-3,8-diaminewhich could be purified by reverse phase column chromatography. LCMS:245 [M+H⁺].

3. METHODS OF TREATMENT

The present invention provides methods for the treatment of a cellproliferative disorder in a subject in need thereof by administering toa subject in need of such treatment, a therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof. The cellproliferative disorder can be cancer or a precancerous condition. Thepresent invention further provides the use of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, for the preparation of a medicament usefulfor the treatment of a cell proliferative disorder.

The present invention also provides methods of protecting against a cellproliferative disorder in a subject in need thereof by administering atherapeutically effective amount of compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, to a subject in need of such treatment. The cellproliferative disorder can be cancer or a precancerous condition. Thepresent invention also provides the use of compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, for the preparation of a medicament usefulfor the prevention of a cell proliferative disorder.

As used herein, a “subject in need thereof” is a subject having a cellproliferative disorder, or a subject having an increased risk ofdeveloping a cell proliferative disorder relative to the population atlarge. A subject in need thereof can have a precancerous condition.Preferably, a subject in need thereof has cancer. A “subject” includes amammal. The mammal can be e.g., any mammal, e.g., a human, primate,bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or apig. Preferably, the mammal is a human.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe invention encompass a variety of conditions wherein cell division isderegulated. Exemplary cell proliferative disorder include, but are notlimited to, neoplasms, benign tumors, malignant tumors, pre-cancerousconditions, in situ tumors, encapsulated tumors, metastatic tumors,liquid tumors, solid tumors, immunological tumors, hematological tumors,cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidlydividing cells. The term “rapidly dividing cell” as used herein isdefined as any cell that divides at a rate that exceeds or is greaterthan what is expected or observed among neighboring or juxtaposed cellswithin the same tissue. A cell proliferative disorder includes aprecancer or a precancerous condition. A cell proliferative disorderincludes cancer. Preferably, the methods provided herein are used totreat or alleviate a symptom of cancer. The term “cancer” includes solidtumors, as well as, hematologic tumors and/or malignancies. A “precancercell” or “precancerous cell” is a cell manifesting a cell proliferativedisorder that is a precancer or a precancerous condition. A “cancercell” or “cancerous cell” is a cell manifesting a cell proliferativedisorder that is a cancer. Any reproducible means of measurement may beused to identify cancer cells or precancerous cells. Cancer cells orprecancerous cells can be identified by histological typing or gradingof a tissue sample (e.g., a biopsy sample). Cancer cells or precancerouscells can be identified through the use of appropriate molecularmarkers.

Exemplary non-cancerous conditions or disorders include, but are notlimited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreaticfibrosis; hepatic fibrosis; acute and chronic renal disease; irritablebowel syndrome; pyresis; restenosis; cerebral malaria; stroke andischemic injury; neural trauma; Alzheimer's disease; Huntington'sdisease; Parkinson's disease; acute and chronic pain; allergic rhinitis;allergic conjunctivitis; chronic heart failure; acute coronary syndrome;cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter'ssyndrome; acute synovitis; muscle degeneration, bursitis; tendonitis;tenosynovitis; herniated, ruptures, or prolapsed intervertebral disksyndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonarysarcosis; bone resorption diseases, such as osteoporosis;graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; and diabetes mellitus.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, appendix cancer, childhoodcerebellar astrocytoma, childhood cerebral astrocytoma, basal cellcarcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bileduct cancer, intrahepatic bile duct cancer, bladder cancer, uringarybladder cancer, bone and joint cancer, osteosarcoma and malignantfibrous histiocytoma, brain cancer, brain tumor, brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodeimaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous systemcancer, nervous system lymphoma, central nervous system cancer, centralnervous system lymphoma, cervical cancer, childhood cancers, chroniclymphocytic leukemia, chronic myelogenous leukemia, chronicmyeloproliferative disorders, colon cancer, colorectal cancer, cutaneousT-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Seziary Syndrome,endometrial cancer, esophageal cancer, extracranial germ cell tumor,extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer,intraocular melanoma, retinoblastoma, gallbladder cancer, gastric(stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST), germ cell tumor, ovarian germ cell tumor,gestational trophoblastic tumor glioma, head and neck cancer,hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, ocular cancer, islet cell tumors (endocrinepancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer,laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, lip and oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell lung cancer, AIDS-relatedlymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma,Waldenstram macroglobulinemia, medulloblastoma, melanoma, intraocular(eye) melanoma, merkel cell carcinoma, mesothelioma malignant,mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer ofthe tongue, multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostatecancer, rectal cancer, renal pelvis and ureter, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewingfamily of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterinecancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer(melanoma), merkel cell skin carcinoma, small intestine cancer, softtissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, testicular cancer,throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter and otherurinary organs, gestational trophoblastic tumor, urethral cancer,endometrial uterine cancer, uterine sarcoma, uterine corpus cancer,vaginal cancer, vulvar cancer, and Wilm's Tumor.

A “cell proliferative disorder of the hematologic system” is a cellproliferative disorder involving cells of the hematologic system. A cellproliferative disorder of the hematologic system can include lymphoma,leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benignmonoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoidpapulosis, polycythemia vera, chronic myelocytic leukemia, agnogenicmyeloid metaplasia, and essential thrombocythemia. A cell proliferativedisorder of the hematologic system can include hyperplasia, dysplasia,and metaplasia of cells of the hematologic system. Preferably,compositions of the present invention may be used to treat a cancerselected from the group consisting of a hematologic cancer of thepresent invention or a hematologic cell proliferative disorder of thepresent invention. A hematologic cancer of the present invention caninclude multiple myeloma, lymphoma (including Hodgkin's lymphoma,non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas oflymphocytic and cutaneous origin), leukemia (including childhoodleukemia, hairy-cell leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia, chronic lymphocytic leukemia, chronic myelocyticleukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloidneoplasms and mast cell neoplasms.

A “cell proliferative disorder of the lung” is a cell proliferativedisorder involving cells of the lung. Cell proliferative disorders ofthe lung can include all forms of cell proliferative disorders affectinglung cells. Cell proliferative disorders of the lung can include lungcancer, a precancer or precancerous condition of the lung, benigngrowths or lesions of the lung, and malignant growths or lesions of thelung, and metastatic lesions in tissue and organs in the body other thanthe lung. Preferably, compositions of the present invention may be usedto treat lung cancer or cell proliferative disorders of the lung. Lungcancer can include all forms of cancer of the lung. Lung cancer caninclude malignant lung neoplasms, carcinoma in situ, typical carcinoidtumors, and atypical carcinoid tumors. Lung cancer can include smallcell lung cancer (“SCLC”), non-small cell lung cancer (“NSCLC”),squamous cell carcinoma, adenocarcinoma, small cell carcinoma, largecell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lungcancer can include “scar carcinoma”, bronchioalveolar carcinoma, giantcell carcinoma, spindle cell carcinoma, and large cell neuroendocrinecarcinoma. Lung cancer can include lung neoplasms having histologic andultrastructual heterogeneity (e.g., mixed cell types).

Cell proliferative disorders of the lung can include all forms of cellproliferative disorders affecting lung cells. Cell proliferativedisorders of the lung can include lung cancer, precancerous conditionsof the lung. Cell proliferative disorders of the lung can includehyperplasia, metaplasia, and dysplasia of the lung. Cell proliferativedisorders of the lung can include asbestos-induced hyperplasia, squamousmetaplasia, and benign reactive mesothelial metaplasia. Cellproliferative disorders of the lung can include replacement of columnarepithelium with stratified squamous epithelium, and mucosal dysplasia.Individuals exposed to inhaled injurious environmental agents such ascigarette smoke and asbestos may be at increased risk for developingcell proliferative disorders of the lung. Prior lung diseases that maypredispose individuals to development of cell proliferative disorders ofthe lung can include chronic interstitial lung disease, necrotizingpulmonary disease, scleroderma, rheumatoid disease, sarcoidosis,interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathicpulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, andHodgkin's disease.

A “cell proliferative disorder of the colon” is a cell proliferativedisorder involving cells of the colon. Preferably, the cellproliferative disorder of the colon is colon cancer. Preferably,compositions of the present invention may be used to treat colon canceror cell proliferative disorders of the colon. Colon cancer can includeall forms of cancer of the colon. Colon cancer can include sporadic andhereditary colon cancers. Colon cancer can include malignant colonneoplasms, carcinoma in situ, typical carcinoid tumors, and atypicalcarcinoid tumors. Colon cancer can include adenocarcinoma, squamous cellcarcinoma, and adenosquamous cell carcinoma. Colon cancer can beassociated with a hereditary syndrome selected from the group consistingof hereditary nonpolyposis colorectal cancer, familial adenomatouspolyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndromeand juvenile polyposis. Colon cancer can be caused by a hereditarysyndrome selected from the group consisting of hereditary nonpolyposiscolorectal cancer, familial adenomatous polyposis, Gardner's syndrome,Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.

Cell proliferative disorders of the colon can include all forms of cellproliferative disorders affecting colon cells. Cell proliferativedisorders of the colon can include colon cancer, precancerous conditionsof the colon, adenomatous polyps of the colon and metachronous lesionsof the colon. A cell proliferative disorder of the colon can includeadenoma. Cell proliferative disorders of the colon can be characterizedby hyperplasia, metaplasia, and dysplasia of the colon. Prior colondiseases that may predispose individuals to development of cellproliferative disorders of the colon can include prior colon cancer.Current disease that may predispose individuals to development of cellproliferative disorders of the colon can include Crohn's disease andulcerative colitis. A cell proliferative disorder of the colon can beassociated with a mutation in a gene selected from the group consistingof p53, ras, FAP and DCC. An individual can have an elevated risk ofdeveloping a cell proliferative disorder of the colon due to thepresence of a mutation in a gene selected from the group consisting ofp53, ras, FAP and DCC.

A “cell proliferative disorder of the pancreas” is a cell proliferativedisorder involving cells of the pancreas. Cell proliferative disordersof the pancreas can include all forms of cell proliferative disordersaffecting pancreatic cells. Cell proliferative disorders of the pancreascan include pancreas cancer, a precancer or precancerous condition ofthe pancreas, hyperplasia of the pancreas, and dysaplasia of thepancreas, benign growths or lesions of the pancreas, and malignantgrowths or lesions of the pancreas, and metastatic lesions in tissue andorgans in the body other than the pancreas. Pancreatic cancer includesall forms of cancer of the pancreas. Pancreatic cancer can includeductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cellcarcinoma, mucinous adenocarcinoma, osteoclast-like giant cellcarcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassifiedlarge cell carcinoma, small cell carcinoma, pancreatoblastoma, papillaryneoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serouscystadenoma. Pancreatic cancer can also include pancreatic neoplasmshaving histologic and ultrastructual heterogeneity (e.g., mixed celltypes).

A “cell proliferative disorder of the prostate” is a cell proliferativedisorder involving cells of the prostate. Cell proliferative disordersof the prostate can include all forms of cell proliferative disordersaffecting prostate cells. Cell proliferative disorders of the prostatecan include prostate cancer, a precancer or precancerous condition ofthe prostate, benign growths or lesions of the prostate, and malignantgrowths or lesions of the prostate, and metastatic lesions in tissue andorgans in the body other than the prostate. Cell proliferative disordersof the prostate can include hyperplasia, metaplasia, and dysplasia ofthe prostate.

A “cell proliferative disorder of the skin” is a cell proliferativedisorder involving cells of the skin. Cell proliferative disorders ofthe skin can include all forms of cell proliferative disorders affectingskin cells. Cell proliferative disorders of the skin can include aprecancer or precancerous condition of the skin, benign growths orlesions of the skin, melanoma, malignant melanoma and other malignantgrowths or lesions of the skin, and metastatic lesions in tissue andorgans in the body other than the skin. Cell proliferative disorders ofthe skin can include hyperplasia, metaplasia, and dysplasia of the skin.

A “cell proliferative disorder of the ovary” is a cell proliferativedisorder involving cells of the ovary. Cell proliferative disorders ofthe ovary can include all forms of cell proliferative disordersaffecting cells of the ovary. Cell proliferative disorders of the ovarycan include a precancer or precancerous condition of the ovary, benigngrowths or lesions of the ovary, ovarian cancer, malignant growths orlesions of the ovary, and metastatic lesions in tissue and organs in thebody other than the ovary. Cell proliferative disorders of the skin caninclude hyperplasia, metaplasia, and dysplasia of cells of the ovary.

A “cell proliferative disorder of the breast” is a cell proliferativedisorder involving cells of the breast. Cell proliferative disorders ofthe breast can include all forms of cell proliferative disordersaffecting breast cells. Cell proliferative disorders of the breast caninclude breast cancer, a precancer or precancerous condition of thebreast, benign growths or lesions of the breast, and malignant growthsor lesions of the breast, and metastatic lesions in tissue and organs inthe body other than the breast. Cell proliferative disorders of thebreast can include hyperplasia, metaplasia, and dysplasia of the breast.

A cell proliferative disorder of the breast can be a precancerouscondition of the breast. Compositions of the present invention may beused to treat a precancerous condition of the breast. A precancerouscondition of the breast can include atypical hyperplasia of the breast,ductal carcinoma in situ (DCIS), intraductal carcinoma, lobularcarcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer,or carcinoma in situ). A precancerous condition of the breast can bestaged according to the TNM classification scheme as accepted by theAmerican Joint Committee on Cancer (AJCC), where the primary tumor (T)has been assigned a stage of T0 or Tis; and where the regional lymphnodes (N) have been assigned a stage of N0; and where distant metastasis(M) has been assigned a stage of M0.

The cell proliferative disorder of the breast can be breast cancer.Preferably, compositions of the present invention may be used to treatbreast cancer. Breast cancer includes all forms of cancer of the breast.Breast cancer can include primary epithelial breast cancers. Breastcancer can include cancers in which the breast is involved by othertumors such as lymphoma, sarcoma or melanoma. Breast cancer can includecarcinoma of the breast, ductal carcinoma of the breast, lobularcarcinoma of the breast, undifferentiated carcinoma of the breast,cystosarcoma phyllodes of the breast, angiosarcoma of the breast, andprimary lymphoma of the breast. Breast cancer can include Stage I, II,IIIA, IIIB, IIIC and IV breast cancer. Ductal carcinoma of the breastcan include invasive carcinoma, invasive carcinoma in situ withpredominant intraductal component, inflammatory breast cancer, and aductal carcinoma of the breast with a histologic type selected from thegroup consisting of comedo, mucinous (colloid), medullary, medullarywith lymphcytic infiltrate, papillary, scirrhous, and tubular. Lobularcarcinoma of the breast can include invasive lobular carcinoma withpredominant in situ component, invasive lobular carcinoma, andinfiltrating lobular carcinoma. Breast cancer can include Paget'sdisease, Paget's disease with intraductal carcinoma, and Paget's diseasewith invasive ductal carcinoma. Breast cancer can include breastneoplasms having histologic and ultrastructual heterogeneity (e.g.,mixed cell types).

Preferably, compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, maybe used to treat breast cancer. A breast cancer that is to be treatedcan include familial breast cancer. A breast cancer that is to betreated can include sporadic breast cancer. A breast cancer that is tobe treated can arise in a male subject. A breast cancer that is to betreated can arise in a female subject. A breast cancer that is to betreated can arise in a premenopausal female subject or a postmenopausalfemale subject. A breast cancer that is to be treated can arise in asubject equal to or older than 30 years old, or a subject younger than30 years old. A breast cancer that is to be treated has arisen in asubject equal to or older than 50 years old, or a subject younger than50 years old. A breast cancer that is to be treated can arise in asubject equal to or older than 70 years old, or a subject younger than70 years old.

A breast cancer that is to be treated can be typed to identify afamilial or spontaneous mutation in BRCA1, BRCA2, or p53. A breastcancer that is to be treated can be typed as having a HER2/neu geneamplification, as overexpressing HER2/neu, or as having a low,intermediate or high level of HER2/neu expression. A breast cancer thatis to be treated can be typed for a marker selected from the groupconsisting of estrogen receptor (ER), progesterone receptor (PR), humanepidermal growth factor receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met.A breast cancer that is to be treated can be typed as ER-unknown,ER-rich or ER-poor. A breast cancer that is to be treated can be typedas ER-negative or ER-positive. ER-typing of a breast cancer may beperformed by any reproducible means. ER-typing of a breast cancer may beperformed as set forth in Onkologie 27: 175-179 (2004). A breast cancerthat is to be treated can be typed as PR-unknown, PR-rich or PR-poor. Abreast cancer that is to be treated can be typed as PR-negative orPR-positive. A breast cancer that is to be treated can be typed asreceptor positive or receptor negative. A breast cancer that is to betreated can be typed as being associated with elevated blood levels ofCA 15-3, or CA 27-29, or both.

A breast cancer that is to be treated can include a localized tumor ofthe breast. A breast cancer that is to be treated can include a tumor ofthe breast that is associated with a negative sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with a positive sentinel lymph node (SLN)biopsy. A breast cancer that is to be treated can include a tumor of thebreast that is associated with one or more positive axillary lymphnodes, where the axillary lymph nodes have been staged by any applicablemethod. A breast cancer that is to be treated can include a tumor of thebreast that has been typed as having nodal negative status (e.g.,node-negative) or nodal positive status (e.g., node-positive). A breastcancer that is to be treated can include a tumor of the breast that hasmetastasized to other locations in the body. A breast cancer that is tobe treated can be classified as having metastasized to a locationselected from the group consisting of bone, lung, liver, or brain. Abreast cancer that is to be treated can be classified according to acharacteristic selected from the group consisting of metastatic,localized, regional, local-regional, locally advanced, distant,multicentric, bilateral, ipsilateral, contralateral, newly diagnosed,recurrent, and inoperable.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, may be used totreat or prevent a cell proliferative disorder of the breast, or totreat or prevent breast cancer, in a subject having an increased risk ofdeveloping breast cancer relative to the population at large. A subjectwith an increased risk of developing breast cancer relative to thepopulation at large is a female subject with a family history orpersonal history of breast cancer. A subject with an increased risk ofdeveloping breast cancer relative to the population at large is a femalesubject having a germ-line or spontaneous mutation in BRCA1 or BRCA2, orboth. A subject with an increased risk of developing breast cancerrelative to the population at large is a female subject with a familyhistory of breast cancer and a germ-line or spontaneous mutation inBRCA1 or BRCA2, or both. A subject with an increased risk of developingbreast cancer relative to the population at large is a female who isgreater than 30 years old, greater than 40 years old, greater than 50years old, greater than 60 years old, greater than 70 years old, greaterthan 80 years old, or greater than 90 years old. A subject with anincreased risk of developing breast cancer relative to the population atlarge is a subject with atypical hyperplasia of the breast, ductalcarcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma insitu (LCIS), lobular neoplasia, or a stage 0 growth or lesion of thebreast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ).

A breast cancer that is to be treated can histologically gradedaccording to the Scarff-Bloom-Richardson system, wherein a breast tumorhas been assigned a mitosis count score of 1, 2, or 3; a nuclearpleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or3; and a total Scarff-Bloom-Richardson score of between 3 and 9. Abreast cancer that is to be treated can be assigned a tumor gradeaccording to the International Consensus Panel on the Treatment ofBreast Cancer selected from the group consisting of grade 1, grade 1-2,grade 2, grade 2-3, or grade 3.

A cancer that is to be treated can be staged according to the AmericanJoint Committee on Cancer (AJCC) TNM classification system, where thetumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2,T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N)have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, orN3c; and where distant metastasis (M) can be assigned a stage of MX, M0,or M1. A cancer that is to be treated can be staged according to anAmerican Joint Committee on Cancer (AJCC) classification as Stage I,Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Acancer that is to be treated can be assigned a grade according to anAJCC classification as Grade GX (e.g., grade cannot be assessed), Grade1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can bestaged according to an AJCC pathologic classification (pN) of pNX, pN0,PN0 (I−), PN0 (I+), PN0 (mol−), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b,PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

A cancer that is to be treated can include a tumor that has beendetermined to be less than or equal to about 2 centimeters in diameter.A cancer that is to be treated can include a tumor that has beendetermined to be from about 2 to about 5 centimeters in diameter. Acancer that is to be treated can include a tumor that has beendetermined to be greater than or equal to about 3 centimeters indiameter. A cancer that is to be treated can include a tumor that hasbeen determined to be greater than 5 centimeters in diameter. A cancerthat is to be treated can be classified by microscopic appearance aswell differentiated, moderately differentiated, poorly differentiated,or undifferentiated. A cancer that is to be treated can be classified bymicroscopic appearance with respect to mitosis count (e.g., amount ofcell division) or nuclear pleiomorphism (e.g., change in cells). Acancer that is to be treated can be classified by microscopic appearanceas being associated with areas of necrosis (e.g., areas of dying ordegenerating cells). A cancer that is to be treated can be classified ashaving an abnormal karyotype, having an abnormal number of chromosomes,or having one or more chromosomes that are abnormal in appearance. Acancer that is to be treated can be classified as being aneuploid,triploid, tetraploid, or as having an altered ploidy. A cancer that isto be treated can be classified as having a chromosomal translocation,or a deletion or duplication of an entire chromosome, or a region ofdeletion, duplication or amplification of a portion of a chromosome.

A cancer that is to be treated can be evaluated by DNA cytometry, flowcytometry, or image cytometry. A cancer that is to be treated can betyped as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cellsin the synthesis stage of cell division (e.g., in S phase of celldivision). A cancer that is to be treated can be typed as having a lowS-phase fraction or a high S-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter is in direct contact with acell, or is close enough to induce a desired biological effect in acell.

As used herein, “candidate compound” refers to a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, that has been or will be tested in one ormore in vitro or in vivo biological assays, in order to determine ifthat compound is likely to elicit a desired biological or medicalresponse in a cell, tissue, system, animal or human that is being soughtby a researcher or clinician. A candidate compound is a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof. The biological or medicalresponse can be the treatment of cancer. The biological or medicalresponse can be treatment or prevention of a cell proliferativedisorder. In vitro or in vivo biological assays can include, but are notlimited to, enzymatic activity assays, electrophoretic mobility shiftassays, reporter gene assays, in vitro cell viability assays, and theassays described herein.

As used herein, “monotherapy” refers to the administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with oneof the compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, to asubject in need of treatment of cancer. Monotherapy may be contrastedwith combination therapy, in which a combination of multiple activecompounds is administered, preferably with each component of thecombination present in a therapeutically effective amount. In oneaspect, monotherapy with a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is more effective than combination therapy in inducinga desired biological effect.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, to alleviate the symptoms or complicationsof a disease, condition or disorder, or to eliminate the disease,condition or disorder.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, can also beused to prevent a disease, condition or disorder. As used herein,“preventing” or “prevent” describes reducing or eliminating the onset ofthe symptoms or complications of the disease, condition or disorder.

As used herein, the term “alleviate” is meant to describe a process bywhich the severity of a sign or symptom of a disorder is decreased.Importantly, a sign or symptom can be alleviated without beingeliminated. In a preferred embodiment, the administration ofpharmaceutical compositions of the invention leads to the elimination ofa sign or symptom, however, elimination is not required. Effectivedosages are expected to decrease the severity of a sign or symptom. Forinstance, a sign or symptom of a disorder such as cancer, which canoccur in multiple locations, is alleviated if the severity of the canceris decreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potentialof cancer to transform from a precancerous, or benign, state into amalignant state. Alternatively, or in addition, severity is meant todescribe a cancer stage, for example, according to the TNM system(accepted by the International Union Against Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC)) or by other art-recognizedmethods. Cancer stage refers to the extent or severity of the cancer,based on factors such as the location of the primary tumor, tumor size,number of tumors, and lymph node involvement (spread of cancer intolymph nodes). Alternatively, or in addition, severity is meant todescribe the tumor grade by art-recognized methods (see, National CancerInstitute, www.cancer.gov). Tumor grade is a system used to classifycancer cells in terms of how abnormal they look under a microscope andhow quickly the tumor is likely to grow and spread. Many factors areconsidered when determining tumor grade, including the structure andgrowth pattern of the cells. The specific factors used to determinetumor grade vary with each type of cancer. Severity also describes ahistologic grade, also called differentiation, which refers to how muchthe tumor cells resemble normal cells of the same tissue type (see,National Cancer Institute, www.cancer.gov). Furthermore, severitydescribes a nuclear grade, which refers to the size and shape of thenucleus in tumor cells and the percentage of tumor cells that aredividing (see, National Cancer Institute, www.cancer.gov).

In another aspect of the invention, severity describes the degree towhich a tumor has secreted growth factors, degraded the extracellularmatrix, become vascularized, lost adhesion to juxtaposed tissues, ormetastasized. Moreover, severity describes the number of locations towhich a primary tumor has metastasized. Finally, severity includes thedifficulty of treating tumors of varying types and locations. Forexample, inoperable tumors, those cancers which have greater access tomultiple body systems (hematological and immunological tumors), andthose which are the most resistant to traditional treatments areconsidered most severe. In these situations, prolonging the lifeexpectancy of the subject and/or reducing pain, decreasing theproportion of cancerous cells or restricting cells to one system, andimproving cancer stage/tumor grade/histological grade/nuclear grade areconsidered alleviating a sign or symptom of the cancer.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body. But signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

Cancer is a group of diseases that may cause almost any sign or symptom.The signs and symptoms will depend on where the cancer is, the size ofthe cancer, and how much it affects the nearby organs or structures. Ifa cancer spreads (metastasizes), then symptoms may appear in differentparts of the body.

As a cancer grows, it begins to push on nearby organs, blood vessels,and nerves. This pressure creates some of the signs and symptoms ofcancer. If the cancer is in a critical area, such as certain parts ofthe brain, even the smallest tumor can cause early symptoms.

But sometimes cancers start in places where it does not cause anysymptoms until the cancer has grown quite large. Pancreas cancers, forexample, do not usually grow large enough to be felt from the outside ofthe body. Some pancreatic cancers do not cause symptoms until they beginto grow around nearby nerves (this causes a backache). Others growaround the bile duct, which blocks the flow of bile and leads to ayellowing of the skin known as jaundice. By the time a pancreatic cancercauses these signs or symptoms, it has usually reached an advancedstage.

A cancer may also cause symptoms such as fever, fatigue, or weight loss.This may be because cancer cells use up much of the body's energy supplyor release substances that change the body's metabolism. Or the cancermay cause the immune system to react in ways that produce thesesymptoms.

Sometimes, cancer cells release substances into the bloodstream thatcause symptoms not usually thought to result from cancers. For example,some cancers of the pancreas can release substances which cause bloodclots to develop in veins of the legs. Some lung cancers makehormone-like substances that affect blood calcium levels, affectingnerves and muscles and causing weakness and dizziness

Cancer presents several general signs or symptoms that occur when avariety of subtypes of cancer cells are present. Most people with cancerwill lose weight at some time with their disease. An unexplained(unintentional) weight loss of 10 pounds or more may be the first signof cancer, particularly cancers of the pancreas, stomach, esophagus, orlung.

Fever is very common with cancer, but is more often seen in advanceddisease. Almost all patients with cancer will have fever at some time,especially if the cancer or its treatment affects the immune system andmakes it harder for the body to fight infection. Less often, fever maybe an early sign of cancer, such as with leukemia or lymphoma.

Fatigue may be an important symptom as cancer progresses. It may happenearly, though, in cancers such as with leukemia, or if the cancer iscausing an ongoing loss of blood, as in some colon or stomach cancers.

Pain may be an early symptom with some cancers such as bone cancers ortesticular cancer. But most often pain is a symptom of advanced disease.

Along with cancers of the skin (see next section), some internal cancerscan cause skin signs that can be seen. These changes include the skinlooking darker (hyperpigmentation), yellow (jaundice), or red(erythema); itching; or excessive hair growth.

Alternatively, or in addition, cancer subtypes present specific signs orsymptoms. Changes in bowel habits or bladder function could indicatecancer. Long-term constipation, diarrhea, or a change in the size of thestool may be a sign of colon cancer. Pain with urination, blood in theurine, or a change in bladder function (such as more frequent or lessfrequent urination) could be related to bladder or prostate cancer.

Changes in skin condition or appearance of a new skin condition couldindicate cancer. Skin cancers may bleed and look like sores that do notheal. A long-lasting sore in the mouth could be an oral cancer,especially in patients who smoke, chew tobacco, or frequently drinkalcohol. Sores on the penis or vagina may either be signs of infectionor an early cancer.

Unusual bleeding or discharge could indicate cancer. Unusual bleedingcan happen in either early or advanced cancer. Blood in the sputum(phlegm) may be a sign of lung cancer. Blood in the stool (or a dark orblack stool) could be a sign of colon or rectal cancer. Cancer of thecervix or the endometrium (lining of the uterus) can cause vaginalbleeding. Blood in the urine may be a sign of bladder or kidney cancer.A bloody discharge from the nipple may be a sign of breast cancer.

A thickening or lump in the breast or in other parts of the body couldindicate the presence of a cancer. Many cancers can be felt through theskin, mostly in the breast, testicle, lymph nodes (glands), and the softtissues of the body. A lump or thickening may be an early or late signof cancer. Any lump or thickening could be indicative of cancer,especially if the formation is new or has grown in size.

Indigestion or trouble swallowing could indicate cancer. While thesesymptoms commonly have other causes, indigestion or swallowing problemsmay be a sign of cancer of the esophagus, stomach, or pharynx (throat).

Recent changes in a wart or mole could be indicative of cancer. Anywart, mole, or freckle that changes in color, size, or shape, or losesits definite borders indicates the potential development of cancer. Forexample, the skin lesion may be a melanoma.

A persistent cough or hoarseness could be indicative of cancer. A coughthat does not go away may be a sign of lung cancer. Hoarseness can be asign of cancer of the larynx (voice box) or thyroid.

While the signs and symptoms listed above are the more common ones seenwith cancer, there are many others that are less common and are notlisted here. However, all art-recognized signs and symptoms of cancerare contemplated and encompassed by the instant invention.

Treating cancer can result in a reduction in size of a tumor. Areduction in size of a tumor may also be referred to as “tumorregression”. Preferably, after treatment, tumor size is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorsize is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. The size of a tumor may be measured as a diameter of thetumor.

Treating cancer can result in a reduction in tumor volume. Preferably,after treatment, tumor volume is reduced by 5% or greater relative toits size prior to treatment; more preferably, tumor volume is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75% or greater. Tumor volume may bemeasured by any reproducible means of measurement.

Treating cancer results in a decrease in number of tumors. Preferably,after treatment, tumor number is reduced by 5% or greater relative tonumber prior to treatment; more preferably, tumor number is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. Number of tumors may bemeasured by any reproducible means of measurement. The number of tumorsmay be measured by counting tumors visible to the naked eye or at aspecified magnification. Preferably, the specified magnification is 2×,3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in a decrease in number of metastatic lesionsin other tissues or organs distant from the primary tumor site.Preferably, after treatment, the number of metastatic lesions is reducedby 5% or greater relative to number prior to treatment; more preferably,the number of metastatic lesions is reduced by 10% or greater; morepreferably, reduced by 20% or greater; more preferably, reduced by 30%or greater; more preferably, reduced by 40% or greater; even morepreferably, reduced by 50% or greater; and most preferably, reduced bygreater than 75%. The number of metastatic lesions may be measured byany reproducible means of measurement. The number of metastatic lesionsmay be measured by counting metastatic lesions visible to the naked eyeor at a specified magnification. Preferably, the specified magnificationis 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population receivingcarrier alone. Preferably, the average survival time is increased bymore than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population ofuntreated subjects. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in increase in average survival time of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingcarrier alone. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to an untreatedpopulation. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to a populationreceiving monotherapy with a drug that is not a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof. Preferably, the mortality rate isdecreased by more than 2%; more preferably, by more than 5%; morepreferably, by more than 10%; and most preferably, by more than 25%. Adecrease in the mortality rate of a population of treated subjects maybe measured by any reproducible means. A decrease in the mortality rateof a population may be measured, for example, by calculating for apopulation the average number of disease-related deaths per unit timefollowing initiation of treatment with an active compound. A decrease inthe mortality rate of a population may also be measured, for example, bycalculating for a population the average number of disease-relateddeaths per unit time following completion of a first round of treatmentwith an active compound.

Treating cancer can result in a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5%relative to number prior to treatment; more preferably, tumor growthrate is reduced by at least 10%; more preferably, reduced by at least20%; more preferably, reduced by at least 30%; more preferably, reducedby at least 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. Tumor growth rate may be measured by any reproducible meansof measurement. Tumor growth rate can be measured according to a changein tumor diameter per unit time.

Treating cancer can result in a decrease in tumor regrowth. Preferably,after treatment, tumor regrowth is less than 5%; more preferably, tumorregrowth is less than 10%; more preferably, less than 20%; morepreferably, less than 30%; more preferably, less than 40%; morepreferably, less than 50%; even more preferably, less than 50%; and mostpreferably, less than 75%. Tumor regrowth may be measured by anyreproducible means of measurement. Tumor regrowth is measured, forexample, by measuring an increase in the diameter of a tumor after aprior tumor shrinkage that followed treatment. A decrease in tumorregrowth is indicated by failure of tumors to reoccur after treatmenthas stopped.

Treating or preventing a cell proliferative disorder can result in areduction in the rate of cellular proliferation. Preferably, aftertreatment, the rate of cellular proliferation is reduced by at least 5%;more preferably, by at least 10%; more preferably, by at least 20%; morepreferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The rate of cellular proliferation maybe measured by any reproducible means of measurement. The rate ofcellular proliferation is measured, for example, by measuring the numberof dividing cells in a tissue sample per unit time.

Treating or preventing a cell proliferative disorder can result in areduction in the proportion of proliferating cells. Preferably, aftertreatment, the proportion of proliferating cells is reduced by at least5%; more preferably, by at least 10%; more preferably, by at least 20%;more preferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The proportion of proliferating cellsmay be measured by any reproducible means of measurement. Preferably,the proportion of proliferating cells is measured, for example, byquantifying the number of dividing cells relative to the number ofnondividing cells in a tissue sample. The proportion of proliferatingcells can be equivalent to the mitotic index.

Treating or preventing a cell proliferative disorder can result in adecrease in size of an area or zone of cellular proliferation.Preferably, after treatment, size of an area or zone of cellularproliferation is reduced by at least 5% relative to its size prior totreatment; more preferably, reduced by at least 10%; more preferably,reduced by at least 20%; more preferably, reduced by at least 30%; morepreferably, reduced by at least 40%; more preferably, reduced by atleast 50%; even more preferably, reduced by at least 50%; and mostpreferably, reduced by at least 75%. Size of an area or zone of cellularproliferation may be measured by any reproducible means of measurement.The size of an area or zone of cellular proliferation may be measured asa diameter or width of an area or zone of cellular proliferation.

Treating or preventing a cell proliferative disorder can result in adecrease in the number or proportion of cells having an abnormalappearance or morphology. Preferably, after treatment, the number ofcells having an abnormal morphology is reduced by at least 5% relativeto its size prior to treatment; more preferably, reduced by at least10%; more preferably, reduced by at least 20%; more preferably, reducedby at least 30%; more preferably, reduced by at least 40%; morepreferably, reduced by at least 50%; even more preferably, reduced by atleast 50%; and most preferably, reduced by at least 75%. An abnormalcellular appearance or morphology may be measured by any reproduciblemeans of measurement. An abnormal cellular morphology can be measured bymicroscopy, e.g., using an inverted tissue culture microscope. Anabnormal cellular morphology can take the form of nuclear pleiomorphism.

As used herein, the term “selectively” means tending to occur at ahigher frequency in one population than in another population. Thecompared populations can be cell populations. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, acts selectively on a canceror precancerous cell but not on a normal cell. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, acts selectively to modulateone molecular target (e.g., a target kinase) but does not significantlymodulate another molecular target (e.g., a non-target kinase). Theinvention also provides a method for selectively inhibiting the activityof an enzyme, such as a kinase. Preferably, an event occurs selectivelyin population A relative to population B if it occurs greater than twotimes more frequently in population A as compared to population B. Anevent occurs selectively if it occurs greater than five times morefrequently in population A. An event occurs selectively if it occursgreater than ten times more frequently in population A; more preferably,greater than fifty times; even more preferably, greater than 100 times;and most preferably, greater than 1000 times more frequently inpopulation A as compared to population B. For example, cell death wouldbe said to occur selectively in cancer cells if it occurred greater thantwice as frequently in cancer cells as compared to normal cells.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, can modulatethe activity of a molecular target (e.g., a target kinase). Modulatingrefers to stimulating or inhibiting an activity of a molecular target.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,modulates the activity of a molecular target if it stimulates orinhibits the activity of the molecular target by at least 2-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. Morepreferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,modulates the activity of a molecular target if it stimulates orinhibits the activity of the molecular target by at least 5-fold, atleast 10-fold, at least 20-fold, at least 50-fold, at least 100-foldrelative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. The activityof a molecular target may be measured by any reproducible means. Theactivity of a molecular target may be measured in vitro or in vivo. Forexample, the activity of a molecular target may be measured in vitro byan enzymatic activity assay or a DNA binding assay, or the activity of amolecular target may be measured in vivo by assaying for expression of areporter gene.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, does notsignificantly modulate the activity of a molecular target if theaddition of the compound does not stimulate or inhibit the activity ofthe molecular target by greater than 10% relative to the activity of themolecular target under the same conditions but lacking only the presenceof said compound.

As used herein, the term “isozyme selective” means preferentialinhibition or stimulation of a first isoform of an enzyme in comparisonto a second isoform of an enzyme (e.g., preferential inhibition orstimulation of a kinase isozyme alpha in comparison to a kinase isozymebeta). Preferably, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, demonstrates a minimum of a four fold differential,preferably a ten fold differential, more preferably a fifty folddifferential, in the dosage required to achieve a biological effect.Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof,demonstrates this differential across the range of inhibition, and thedifferential is exemplified at the IC₅₀, i.e., a 50% inhibition, for amolecular target of interest.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, to acell or a subject in need thereof can result in modulation (i.e.,stimulation or inhibition) of an activity of a kinase of interest.

The present invention provides methods to assess biological activity ofa compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof. In one method,an assay based on enzymatic activity can be utilized. In one specificenzymatic activity assay, the enzymatic activity is from a kinase. Asused herein, “kinase” refers to a large class of enzymes which catalyzethe transfer of the γ-phosphate from ATP to the hydroxyl group on theside chain of Ser/Thr or Tyr in proteins and peptides and are intimatelyinvolved in the control of various important cell functions, perhapsmost notably: signal transduction, differentiation, and proliferation.There are estimated to be about 2,000 distinct protein kinases in thehuman body, and although each of these phosphorylate particularprotein/peptide substrates, they all bind the same second substrate ATPin a highly conserved pocket. About 50% of the known oncogene productsare protein tyrosine kinases (PTKs), and their kinase activity has beenshown to lead to cell transformation. Preferably, the kinase assayed isa tyrosine kinase.

A change in enzymatic activity caused by a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, can be measured in the disclosed assays.The change in enzymatic activity can be characterized by the change inthe extent of phosphorylation of certain substrates. As used herein,“phosphorylation” refers to the addition of phosphate groups to asubstrate, including proteins and organic molecules; and, plays animportant role in regulating the biological activities of proteins.Preferably, the phosphorylation assayed and measured involves theaddition of phosphate groups to tyrosine residues. The substrate can bea peptide or protein.

In some assays, immunological reagents, e.g., antibodies and antigens,are employed. Fluorescence can be utilized in the measurement ofenzymatic activity in some assays. As used herein, “fluorescence” refersto a process through which a molecule emits a photon as a result ofabsorbing an incoming photon of higher energy by the same molecule.Specific methods for assessing the biological activity of the disclosedcompounds are described in the examples.

As used herein, an activity of c-Met refers to any biological functionor activity that is carried out by c-Met. For example, a function ofc-Met includes phosphorylation of downstream target proteins. Otherfunctions of c-Met include autophosphorylation, binding of adaptorproteins such as Gab-1, Grb-2, Shc, SHP2 and c-Cbl, and activation ofsignal transducers such as Ras, Src, PI3K, PLC-γ, STATs, ERK1 and 2 andFAK.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, polymorph or solvate thereof, to acell or a subject in need thereof results in modulation (i.e.,stimulation or inhibition) of an activity of an intracellular target(e.g., substrate). Several intracellular targets can be modulated withthe compounds of the present invention, including, but not limited to,adaptor proteins such as Gab-1, Grb-2, Shc, SHP2 and c-Cbl, and signaltransducers such as Ras, Src, PI3K, PLC-γ, STATs, ERK1 and 2 and FAK.

Activating refers to placing a composition of matter (e.g., protein ornucleic acid) in a state suitable for carrying out a desired biologicalfunction. A composition of matter capable of being activated also has anunactivated state. An activated composition of matter may have aninhibitory or stimulatory biological function, or both.

Elevation refers to an increase in a desired biological activity of acomposition of matter (e.g., a protein or a nucleic acid). Elevation mayoccur through an increase in concentration of a composition of matter.

As used herein, “a cell cycle checkpoint pathway” refers to abiochemical pathway that is involved in modulation of a cell cyclecheckpoint. A cell cycle checkpoint pathway may have stimulatory orinhibitory effects, or both, on one or more functions comprising a cellcycle checkpoint. A cell cycle checkpoint pathway is comprised of atleast two compositions of matter, preferably proteins, both of whichcontribute to modulation of a cell cycle checkpoint. A cell cyclecheckpoint pathway may be activated through an activation of one or moremembers of the cell cycle checkpoint pathway. Preferably, a cell cyclecheckpoint pathway is a biochemical signaling pathway.

As used herein, “cell cycle checkpoint regulator” refers to acomposition of matter that can function, at least in part, in modulationof a cell cycle checkpoint. A cell cycle checkpoint regulator may havestimulatory or inhibitory effects, or both, on one or more functionscomprising a cell cycle checkpoint. A cell cycle checkpoint regulatorcan be a protein or not a protein.

Treating cancer or a cell proliferative disorder can result in celldeath, and preferably, cell death results in a decrease of at least 10%in number of cells in a population. More preferably, cell death means adecrease of at least 20%; more preferably, a decrease of at least 30%;more preferably, a decrease of at least 40%; more preferably, a decreaseof at least 50%; most preferably, a decrease of at least 75%. Number ofcells in a population may be measured by any reproducible means. Anumber of cells in a population can be measured by fluorescenceactivated cell sorting (FACS), immunofluorescence microscopy and lightmicroscopy. Methods of measuring cell death are as shown in Li et al.,Proc Natl Acad Sci USA. 100(5): 2674-8, 2003. In an aspect, cell deathoccurs by apoptosis.

Preferably, an effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is not significantly cytotoxic to normal cells. Atherapeutically effective amount of a compound is not significantlycytotoxic to normal cells if administration of the compound in atherapeutically effective amount does not induce cell death in greaterthan 10% of normal cells. A therapeutically effective amount of acompound does not significantly affect the viability of normal cells ifadministration of the compound in a therapeutically effective amountdoes not induce cell death in greater than 10% of normal cells. In anaspect, cell death occurs by apoptosis.

Contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, can induce or activate cell death selectively in cancercells. Administering to a subject in need thereof a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce or activate celldeath selectively in cancer cells. Contacting a cell with a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce cell deathselectively in one or more cells affected by a cell proliferativedisorder. Preferably, administering to a subject in need thereof acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, induces celldeath selectively in one or more cells affected by a cell proliferativedisorder.

The present invention relates to a method of treating or preventingcancer by administering a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, to a subject in need thereof, where administration ofthe compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, results in oneor more of the following: accumulation of cells in G1 and/or S phase ofthe cell cycle, cytotoxicity via cell death in cancer cells without asignificant amount of cell death in normal cells, antitumor activity inanimals with a therapeutic index of at least 2, and activation of a cellcycle checkpoint. As used herein, “therapeutic index” is the maximumtolerated dose divided by the efficacious dose.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3^(rd) edition), Cold SpringHarbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., CurrentProtocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., CurrentProtocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., ThePharmacological Basis of Therapeutics (1975), Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 18^(th) edition (1990).These texts can, of course, also be referred to in making or using anaspect of the invention

As used herein, “combination therapy” or “co-therapy” includes theadministration of a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, and at least a second agent as part of a specifictreatment regimen intended to provide the beneficial effect from theco-action of these therapeutic agents. The beneficial effect of thecombination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” may be, but generally is not, intended toencompass the administration of two or more of these therapeutic agentsas part of separate monotherapy regimens that incidentally andarbitrarily result in the combinations of the present invention.

“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, wherein each therapeuticagent is administered at a different time, as well as administration ofthese therapeutic agents, or at least two of the therapeutic agents, ina substantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected may be administered by intravenous injection while the othertherapeutic agents of the combination may be administered orally.Alternatively, for example, all therapeutic agents may be administeredorally or all therapeutic agents may be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical.

“Combination therapy” also embraces the administration of thetherapeutic agents as described above in further combination with otherbiologically active ingredients and non-drug therapies (e.g., surgery orradiation treatment). Where the combination therapy further comprises anon-drug treatment, the non-drug treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and non-drug treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

A compound of the present invention, or a pharmaceutically acceptablesalt, prodrug, metabolite, analog or derivative thereof, may beadministered in combination with a second chemotherapeutic agent. Thesecond chemotherapeutic agent (also referred to as an anti-neoplasticagent or anti-proliferative agent) can be an alkylating agent; anantibiotic; an anti-metabolite; a detoxifying agent; an interferon; apolyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor;a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTORinhibitor; a multi-kinase inhibitor; a serine/threonine kinaseinhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; ataxane or taxane derivative, an aromatase inhibitor, an anthracycline, amicrotubule targeting drug, a topoisomerase poison drug, an inhibitor ofa molecular target or enzyme (e.g., a kinase inhibitor), a cytidineanalogue drug or any chemotherapeutic, anti-neoplastic oranti-proliferative agent listed inwww.cancer.org/docroot/cdg/cdg_(—)0.asp.

Exemplary alkylating agents include, but are not limited to,cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan(Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU);dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel);ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran);carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide(Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin(Zanosar).

Exemplary antibiotics include, but are not limited to, doxorubicin(Adriamycin); doxorubicin liposomal (Doxil); mitoxantrone (Novantrone);bleomycin (Blenoxane); daunorubicin (Cerubidine); daunorubicin liposomal(DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin(Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin(Nipent); or valrubicin (Valstar).

Exemplary anti-metabolites include, but are not limited to, fluorouracil(Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine(Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine(Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar);cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal(DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine(FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine(Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall);thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

Exemplary detoxifying agents include, but are not limited to, amifostine(Ethyol) or mesna (Mesnex).

Exemplary interferons include, but are not limited to, interferonalfa-2b (Intron A) or interferon alfa-2a (Roferon-A).

Exemplary polyclonal or monoclonal antibodies include, but are notlimited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab(Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab(Vectibix); tositumomab/iodine¹³¹ tositumomab (Bexxar); alemtuzumab(Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab(Mylotarg); eculizumab (Soliris) ordenosumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib(Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva);panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab(Emd7200) or EKB-569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab(Herceptin); lapatinib (Tykerb) or AC-480.

Histone Deacetylase Inhibitors include, but are not limited to,vorinostat (Zolinza).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox;Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron;Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole(Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane(Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole(Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone(Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin);toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron);abarelix (Plenaxis); or testolactone (Teslac).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel(Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin;Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos;VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole;epothilone; vinorelbine (Navelbine); camptothecin (CPT); irinotecan(Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

Exemplary MTOR inhibitors include, but are not limited to, everolimus(Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; orAP23573.

Exemplary multi-kinase inhibitors include, but are not limited to,sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474;PKC-412; motesanib; or AP24534.

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol;seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412;bryostatin; KAI-9803; SF1126; VX-680; Azd1152; Arry-142886 (AZD-6244);SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.

Exemplary tyrosine kinase inhibitors include, but are not limited to,erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib(Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab(Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux);panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath);gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient);dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584);CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

Exemplary VEGF/VEGFR inhibitors include, but are not limited to,bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent);ranibizumab; pegaptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to,paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilonesand navelbine.

Exemplary topoisomerase poison drugs include, but are not limited to,teniposide, etoposide, adriamycin, camptothecin, daunorubicin,dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.

Exemplary taxanes or taxane derivatives include, but are not limited to,paclitaxel and docetaxol.

Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferativeagents include, but are not limited to, altretamine (Hexalen);isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin(Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase(Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine(Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak);porfimer (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid);bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel);arsenic trioxide (Trisenox); verteporfin (Visudyne); mimosine(Leucenol); (1M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 Mpotassium oxonate) or lovastatin.

In another aspect, the second chemotherapeutic agent can be a cytokinesuch as G-CSF (granulocyte colony stimulating factor). In anotheraspect, a compound of the present invention, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, maybe administered in combination with radiation therapy. Radiation therapycan also be administered in combination with a compound of the presentinvention and another chemotherapeutic agent described herein as part ofa multiple agent therapy. In yet another aspect, a compound of thepresent invention, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof, may be administered incombination with standard chemotherapy combinations such as, but notrestricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil),CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycinand cyclophosphamide), FEC (5-fluorouracil, epirubicin, andcyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, andpaclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP),Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molarratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or Camptosar™) orCMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

In preferred embodiments, a compound of the present invention, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, may be administered with an inhibitor of an enzyme,such as a receptor or non-receptor kinase. Receptor and non-receptorkinases of the invention are, for example, tyrosine kinases orserine/threonine kinases. Kinase inhibitors of the invention are smallmolecules, polynucleic acids, polypeptides, or antibodies.

Exemplary kinase inhibitors include, but are not limited to, Bevacizumab(targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab/Erbitux(targets Erb1), Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targetsErb2), Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF),Pegaptanib (targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib(targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2),GW-572016/lapatinib ditosylate (targets HER2/Erb2), Panitumumab/Vectibix(targets EGFR), Vandetinib (targets RET/VEGFR), E7080 (multiple targetsincluding RET and VEGFR), Herceptin (targets HER2/Erb2), PKI-166(targets EGFR), Canertinib/CI-1033 (targets EGFR),Sunitinib/SU-11464/Sutent (targets EGFR and FLT3), Matuzumab/Emd7200(targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR),PKC-412 (targets VEGR and FLT3), Vatalanib/Ptk787/ZK222584 (targetsVEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), MLN518 (targetsFLT3), XL999 (targets FLT3), VX-322 (targets FLT3), Azd0530 (targetsSRC), BMS-354825 (targets SRC), SKI-606 (targets SRC), CP-690 (targetsJAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 (targetsJAK), sorafenib/Nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3,PDGFR-β, KIT, FLT-3, and RET), Dasatinib/Sprycel (BCR/ABL and Src),AC-220 (targets Flt3), AC-480 (targets all HER proteins, “panHER”),Motesanib diphosphate (targets VEGF1-3, PDGFR, and c-kit), Denosumab(targets RANKL, inhibits SRC), AMG888 (targets HER3), and AP24534(multiple targets including Flt3).

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR),Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1),Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK),Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032(targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC),Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K),VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase),Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK),GW681323 (targets MAP/MEK), CC-401 (targets JNK), CEP-1347 (targetsJNK), and PD 332991 (targets CDK).

4. PHARMACEUTICAL COMPOSITIONS

The present invention also provides pharmaceutical compositionscomprising a compound of each of the formulae described herein incombination with at least one pharmaceutically acceptable excipient orcarrier.

A “pharmaceutical composition” is a formulation containing the compoundsof the present invention in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, inhalational, buccal, sublingual, intrapleural,intrathecal, intranasal, and the like. Dosage forms for the topical ortransdermal administration of a compound of this invention includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In one embodiment, the active compound is mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the invention can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the invention may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not so high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician. In a preferred aspect,the disease or condition to be treated is cancer. In another aspect, thedisease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compounds of thepresent invention may be manufactured in a manner that is generallyknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the invention vary depending on theagent, the age, weight, and clinical condition of the recipient patient,and the experience and judgment of the clinician or practitioneradministering the therapy, among other factors affecting the selecteddosage. Generally, the dose should be sufficient to result in slowing,and preferably regressing, the growth of the tumors and also preferablycausing complete regression of the cancer. Dosages can range from about0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects,dosages can range from about 1 mg/kg per day to about 1000 mg/kg perday. In an aspect, the dose will be in the range of about 0.1 mg/day toabout 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day toabout 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about1 g/day, in single, divided, or continuous doses (which dose may beadjusted for the patient's weight in kg, body surface area in m², andage in years). An effective amount of a pharmaceutical agent is thatwhich provides an objectively identifiable improvement as noted by theclinician or other qualified observer. For example, regression of atumor in a patient may be measured with reference to the diameter of atumor. Decrease in the diameter of a tumor indicates regression.Regression is also indicated by failure of tumors to reoccur aftertreatment has stopped. As used herein, the term “dosage effectivemanner” refers to amount of an active compound to produce the desiredbiological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The compounds of the present invention are capable of further formingsalts. All of these forms are also contemplated within the scope of theclaimed invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the compounds of the present invention wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines, alkalior organic salts of acidic residues such as carboxylic acids, and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, but are not limitedto, those derived from inorganic and organic acids selected from2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic,glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic,pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic,salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic,sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurringamine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoicacid, cyclopentane propionic acid, pyruvic acid, malonic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonicacid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, muconic acid, and the like. The present invention also encompassessalts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same salt.

The compounds of the present invention can also be prepared as esters,for example, pharmaceutically acceptable esters. For example, acarboxylic acid function group in a compound can be converted to itscorresponding ester, e.g., a methyl, ethyl or other ester. Also, analcohol group in a compound can be converted to its corresponding ester,e.g., an acetate, propionate or other ester.

The compounds of the present invention can also be prepared as prodrugs,for example, pharmaceutically acceptable prodrugs. The terms “pro-drug”and “prodrug” are used interchangeably herein and refer to any compoundwhich releases an active parent drug in vivo. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.), the compounds of thepresent invention can be delivered in prodrug form. Thus, the presentinvention is intended to cover prodrugs of the presently claimedcompounds, methods of delivering the same and compositions containingthe same. “Prodrugs” are intended to include any covalently bondedcarriers that release an active parent drug of the present invention invivo when such prodrug is administered to a subject. Prodrugs in thepresent invention are prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds of the present invention wherein a hydroxy, amino,sulfhydryl, carboxy or carbonyl group is bonded to any group that may becleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl,free carboxy or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals and enolesters of ketone and aldehyde functional groups in compounds of theinvention, and the like, See Bundegaard, H., Design of Prodrugs, p 1-92,Elesevier, New York-Oxford (1985).

The compounds, or pharmaceutically acceptable salts, esters or prodrugsthereof, are administered orally, nasally, transdermally, pulmonary,inhalationally, buccally, sublingually, intraperintoneally,subcutaneously, intramuscularly, intravenously, rectally,intrapleurally, intrathecally and parenterally. In one embodiment, thecompound is administered orally. One skilled in the art will recognizethe advantages of certain routes of administration.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compoundsof the invention can be found in Remington: the Science and Practice ofPharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995). Inan embodiment, the compounds described herein, and the pharmaceuticallyacceptable salts thereof, are used in pharmaceutical preparations incombination with a pharmaceutically acceptable carrier or diluent.Suitable pharmaceutically acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present invention areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentinvention. The examples do not limit the claimed invention. Based on thepresent disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present invention.

5. EXAMPLES Example 1 Synthesis and Physical Characterization ofRepresentative Compounds of the Present Invention are Shown in Table 2

TABLE 2 Compound LCMS No. Structure ([M + H⁺]) Synthesis 1

331 General Procedure (Step 4) 2

245 General Procedure (Step 5) 3

347 General Procedure (Step 4) 4

357 General Procedure (Step 4) 5

343 General Procedure (Step 4) 6

353 General Procedure (Step 4) 7

377 General Procedure (Step 4) 8

418 General Procedure (Step 4) 9

361 General Procedure (Step 4) 10

403 General Procedure (Step 4) 11

343 General Procedure (Step 4) 12

369 General Procedure (Step 4) 13

347 General Procedure (Step 4) 14

327 General Procedure (Step 4) 15

357 General Procedure (Step 4) 16

361 General Procedure (Step 4) 17

395 General Procedure (Step 4) 18

355 General Procedure (Step 4) 19

341 General Procedure (Step 4) 20

362 General Procedure (Step 4) 21

348 General Procedure (Step 4) 22

383 General Procedure (Step 4) 23

357 General Procedure (Step 4) 24

361 General Procedure (Step 4) 25

356 General Procedure (Step 4) 26

355 General Procedure (Step 4) 27

361 General Procedure (Step 4) 28

359 General Procedure (Step 4) 29

341 General Procedure (Step 4) 30

341 General Procedure (Step 4) 31

401 General Procedure (Step 4) 32

377 General Procedure (Step 4) 33

401 General Procedure (Step 4) 34

353 General Procedure (Step 4) 35

373 General Procedure (Step 4) 36

433 General Procedure (Step 4) 37

357 General Procedure (Step 4) 38

365 General Procedure (Step 4) 39

343 General Procedure (Step 4) 40

341 General Procedure (Step 4) 41

357 General Procedure (Step 4) 42

355 General Procedure (Step 4) 43

313 General Procedure (Step 4) 44

371 General Procedure (Step 4) 45

357 General Procedure (Step 4) 46

373 General Procedure (Step 4) 47

327 General Procedure (Step 4) 48

395 General Procedure (Step 4) 49

375 General Procedure (Step 4) 50

369 General Procedure (Step 4) 51

338 General Procedure (Step 4) 52

391 General Procedure (Step 4) 53

328 General Procedure (Step 4) 54

371 General Procedure (Step 4) 55

437 General Procedure (Step 4) 56

353 General Procedure (Step 4) 57

387 General Procedure (Step 4) 58

371 General Procedure (Step 4) 59

305 General Procedure (Step 4) 60

345 General Procedure (Step 4) 61

403 General Procedure (Step 4) 62

369 General Procedure (Step 4) 63

355 General Procedure (Step 4) 64

371 General Procedure (Step 4) 65

433 General Procedure (Step 4) 66

463 General Procedure (Step 4) 67

347 General Procedure (Step 4) 68

405 General Procedure (Step 4) 69

341 General Procedure (Step 4) 70

293 General Procedure (Step 4) 71

355 General Procedure (Step 4) 72

361 General Procedure (Step 4) 73

355 General Procedure (Step 4) 74

361 General Procedure (Step 4) 75

383 General Procedure (Step 4) 76

348 General Procedure (Step 4) 77

391 General Procedure (Step 4) 78

327 General Procedure (Step 4) 79

328 General Procedure (Step 4) 80

405 General Procedure (Step 4) 81

395 General Procedure (Step 4) 82

471 General Procedure (Step 4) 83

327 General Procedure (Step 4) 84

345 General Procedure (Step 4) 85

393 General Procedure (Step 4) 86

345 General Procedure (Step 4) 87

361 General Procedure (Step 4) 88

385 General Procedure (Step 5) 89

257 General Procedure (Step 5) 90

269 General Procedure (Step 5) 91

255 General Procedure (Step 5) 92

319 General Procedure (Step 5) 93

347 General Procedure (Step 5) 94

259 General Procedure (Step 5) 95

241 General Procedure (Step 5) 96

259 General Procedure (Step 5) 97

283 General Procedure (Step 5) 98

273 General Procedure (Step 5) 99

245 General Procedure (Step 5) 100

309 General Procedure (Step 5) 101

333 General Procedure (Step 5) 102

269 General Procedure (Step 5) 103

255 General Procedure (Step 5) 104

317 General Procedure (Step 5) 105

287 General Procedure (Step 5) 106

291 General Procedure (Step 5) 107

255 General Procedure (Step 5) 108

317 General Procedure (Step 5) 109

261 General Procedure (Step 5) 110

261 General Procedure (Step 5) 111

271 General Procedure (Step 5) 112

241 General Procedure (Step 5) 113

335 General Procedure (Step 5) 114

289 General Procedure (Step 5) 115

289 General Procedure (Step 5) 116

270 General Procedure (Step 5) 117

285 General Procedure (Step 5) 118

241 General Procedure (Step 5) 119

275 General Procedure (Step 5) 120

351 General Procedure (Step 5) 121

245 General Procedure (Step 5) 122

347 General Procedure (Step 5) 123

257 General Procedure (Step 5) 124

271 General Procedure (Step 5) 125

315 General Procedure (Step 5) 126

291 General Procedure (Step 5) 127

279 General Procedure (Step 5) 128

377 General Procedure (Step 5) 129

275 General Procedure (Step 5) 130

281 General Procedure (Step 5) 131

269 General Procedure (Step 5) 132

271 General Procedure (Step 5) 133

301 General Procedure (Step 5) 134

297 General Procedure (Step 5) 135

285 General Procedure (Step 5) 136

255 General Procedure (Step 5) 137

333 General Procedure (Step 5) 138

259 General Procedure (Step 5) 139

269 General Procedure (Step 5) 140

319 General Procedure (Step 5) 141

275 General Procedure (Step 5) 142

305 General Procedure (Step 5) 143

309 General Procedure (Step 5) 144

297 General Procedure (Step 5) 145

267 General Procedure (Step 5) 146

241 General Procedure (Step 5) 147

283 General Procedure (Step 5) 148

309 General Procedure (Step 5) 149

269 General Procedure (Step 5) 150

285 General Procedure (Step 5) 151

271 General Procedure (Step 5) 152

271 General Procedure (Step 5) 153

259 General Procedure (Step 5) 154

291 General Procedure (Step 5) 155

275 General Procedure (Step 5) 156

267 General Procedure (Step 5) 157

241 General Procedure (Step 5) 158

289 General Procedure (Step 5) 159

255 General Procedure (Step 5) 160

295 General Procedure (Step 5) 161

287 General Procedure (Step 5)

Example 2 FGFR2 Kinase Activity Assay

A fluorescent ELISA assay was developed to identify and characterizeinhibitors of FGFR2 kinase. This heterogeneous assay utilized abiotinylated peptide with a tyrosine motif as a substrate and ananti-phospho-tyrosine antibody to measure phosphorylation of thesubstrate. The reaction was initiated by adding a test compound, 37 uMPyk2 substrate (Midwest Biotech, cat. #MBT2383), 12.5 uM ATP (Roche,cat. #11 140 965 001), and 0.5 uM FGFR2 enzyme (Millipore, cat. #14-742)sequentially to a non-binding polypropylene V-well plate. All reagentswere in assay buffer consisting of: 50 mM Tris-HCL, 0.02 mg/mL BSA, 10mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM EGTA, 75 μM ATP, 0.01% NP-40, 2 mM DTT,10% Glycerol. The reaction was incubated for 60 minutes. As the reactionproceeded, FGFR2 phosphorylated tyrosines in the peptide. The reactionmixture was then moved to a blocked streptavidin coated Nunc Maxisorbplate (coated with 100 ng streptavidin from Pierce (cat #15-124) perwell) allowing for the capture of the biotinylated peptide. Peptide wascaptured for 30 minutes at room temperature, the phosphorylation ofpeptide continues during this phase. The reaction was stopped by washingthe Streptavidin plate 6 times with TBST. Phosphorylated peptide wasdetected by adding anti-phospho tyrosine antibody (purchased from CellSignaling, cat. #9411, diluted 1:3000), unbound antibody was removed bywashing 6 times with TBST. Secondary detection was performed usingAlkaline Phosphatase tagged goat anti-mouse antibody (purchased fromPierce, cat. #31320, diluted 1:4000) for one hour. Unbound secondaryantibody was removed by washing 6 times with TBST.

The fluorescent readout was initiated by the addition of PromegaAttophos substrate (purchased from Promega; Kit catalog number: S1000,dilution=6 mg/10 mL), which when dephosphorylated by Alkalinephosphatase emitted a fluorescent signal of 595 nM when excited by asignal 400 nM. This reading was done on the Perkin Elmer Envisionsystem. Compounds which prevent the FGFR2 from phosphorylating thepeptide resulted in a lower fluorescent signal. The signal was directlyproportional to the activity of FGFR2 and compound inhibition of FGFR2was monitored by a decrease in signal.

Table 3 shows the FGFR2 kinase inhibition activity of representativecompounds of the present invention.

TABLE 3 FGFR2 (N549H), Compound inhibition No. Chemical Name @ 30 μM (%)7 isopropyl {8-[(5-chloro-2- 55.5methoxyphenyl)amino][1,2,4]triazolo[4,3- a]pyrazin-3-yl}carbamate 13isopropyl {8-[(2- 50.5chlorophenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 14isopropyl {8-[(2- 82 methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 15 isopropyl {8-[(2- 51methoxybenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 17isopropyl (8-{[4- 68.8(trifluoromethyl)benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 19 isopropyl {8-[(3- 55.2methylbenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 22isopropyl {8-[(4-tert- 100butylbenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 23isopropyl {8-[(2-methoxy-5- 50.9methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 24isopropyl {8-[(3- 65.3chlorobenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 28isopropyl (8-{[2-(4- 51.6 fluorophenyl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 30 isopropyl {8- 56.3[benzyl(methyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 31isopropyl (8-{[2-(3,5- 96.5dimethoxyphenyl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 34 isopropyl [8-(2,3-dihydro-1H-inden-5- 68.7ylamino)[1,2,4]triazolo[4,3-a]pyrazin-3- yl]carbamate 35 isopropyl{8-[(2,4- 57 dimethoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 36 isopropyl (8-{[2-(4- 51.4phenoxyphenyl)ethyl]amino}[1,2,4]triazolo[4,3- a]pyrazin-3-yl)carbamate39 isopropyl {8-[(2- 78.3 methoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 41 isopropyl {8-[(2- 62.5methoxyphenyl)(methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 42 isopropyl (8-{[2-(3- 58.7methylphenyl)ethyl]amino}[1,2,4]triazolo[4,3- a]pyrazin-3-yl)carbamate46 isopropyl {8-[(2,5- 84.6 dimethoxyphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 48 isopropyl (8-{[2- 87(trifluoromethyl)benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 50 isopropyl {8-[(4-tert- 63.6butylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 52isopropyl {8-[(4- 95.1bromophenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 53isopropyl {8-[methyl(pyridin-2- 68.1yl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 56 isopropyl[8-(1H-benzimidazol-2- 64.7 ylamino)[1,2,4]triazolo[4,3-a]pyrazin-3-yl]carbamate 58 isopropyl (8-{[2-(2- 80.6methoxyphenyl)ethyl]amino}[1,2,4]triazolo[4,3- a]pyrazin-3-yl)carbamate59 isopropyl (8-piperidin-1-yl[1,2,4]triazolo[4,3- 82.5a]pyrazin-3-yl)carbamate 61 isopropyl {8-[(biphenyl-4- 100ylmethyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 62isopropyl (8-{[2-(4- 74.2 ethylphenyl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 63 isopropyl {8-[ethyl(2- 75.7methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 64isopropyl {8-[ethyl(5-hydroxy-2- 57.2methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 66isopropyl (8-{[3,5- 58.4bis(trifluoromethyl)benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 67 isopropyl {8-[(3- 119chlorophenyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 69isopropyl {8-[methyl(4- 52.8methylphenyl)amino][1,2,4]triazolo[4,3-a]pyrazin- 3-yl}carbamate 80isopropyl {8-[(2- 51 bromobenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 81 isopropyl (8-{[3- 96.9(trifluoromethyl)benzyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate 82 isopropyl{8-[4-(5-chloro-2-oxo-2,3-dihydro-1H- 65.2benzimidazol-1-yl)piperidin-1-yl][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 84 isopropyl {8-[(2- 84fluorobenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 85isopropyl (8-{[2-(7-methyl-1H-indol-3- 50.6yl)ethyl]amino}[1,2,4]triazolo[4,3-a]pyrazin-3- yl)carbamate 86isopropyl {8-[(3- 88.8fluorobenzyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3- yl}carbamate 87isopropyl {8-[(4- 57.7 chlorophenyl)(methyl)amino][1,2,4]triazolo[4,3-a]pyrazin-3-yl}carbamate 90N⁸-[2-(4-methylphenyl)ethyl][1,2,4]triazolo[4,3- 60.8a]pyrazine-3,8-diamine 92N⁸-(2-bromobenzyl)[1,2,4]triazolo[4,3-a]pyrazine- 59.2 3,8-diamine 93N⁸-[2-(4-phenoxyphenyl)ethyl][1,2,4]triazolo[4,3- 82.9a]pyrazine-3,8-diamine 99N⁸-(3-fluorophenyl)[1,2,4]triazolo[4,3-a]pyrazine- 60.7 3,8-diamine 100N⁸-[4-(trifluoromethyl)benzyl][1,2,4]triazolo[4,3- 66.5a]pyrazine-3,8-diamine 107N⁸-methyl-N⁸-(4-methylphenyl)[1,2,4]triazolo[4,3- 86.1a]pyrazine-3,8-diamine 115N⁸-[2-(4-chlorophenyl)ethyl][1,2,4]triazolo[4,3- 71.6a]pyrazine-3,8-diamine 116N⁸-[4-(dimethylamino)phenyl][1,2,4]triazolo[4,3- 50a]pyrazine-3,8-diamine 118N⁸-(3-methylphenyl)[1,2,4]triazolo[4,3-a]pyrazine- 50.4 3,8-diamine 121N⁸-(2-fluorophenyl)[1,2,4]triazolo[4,3-a]pyrazine- 65.7 3,8-diamine 124N⁸-(2-methoxy-5-methylphenyl)[1,2,4]triazolo[4,3- 73.5a]pyrazine-3,8-diamine 131 N⁸-(2,3-dimethylbenzyl)[1,2,4]triazolo[4,3-65.7 a]pyrazine-3,8-diamine 139N⁸-(4-ethylbenzyl)[1,2,4]triazolo[4,3-a]pyrazine- 96.3 3,8-diamine 140N⁸-(4-bromobenzyl)[1,2,4]triazolo[4,3-a]pyrazine- 52.9 3,8-diamine 142N⁸-(3-bromophenyl)[1,2,4]triazolo[4,3-a]pyrazine- 59.9 3,8-diamine 143N⁸-[2-(trifluoromethyl)benzyl][1,2,4]triazolo[4,3- 73.2a]pyrazine-3,8-diamine 152 N⁸-(4-methoxyphenyl)-N⁸- 109methyl[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine 153N⁸-(2-fluorobenzyl)[1,2,4]triazolo[4,3-a]pyrazine- 72.9 3,8-diamine 154N⁸-(2-chloro-5-methoxyphenyl)[1,2,4]triazolo[4,3- 82.8a]pyrazine-3,8-diamine 155N⁸-(3-chlorophenyl)-N⁸-methyl[1,2,4]triazolo[4,3- 57.4a]pyrazine-3,8-diamine 157N⁸-(2-methylphenyl)[1,2,4]triazolo[4,3-a]pyrazine- 54.6 3,8-diamine 160N⁸-(2,5-dichlorophenyl)[1,2,4]triazolo[4,3- 68.6 a]pyrazine-3,8-diamine

Example 3 MTS Assay

Cells were maintained at 37° C., 5% CO₂ in DMEM media supplemented with1% fetal bovine serum, penicillin/streptomycin and fungizone(Invitrogen). Cells were seeded into 96-well tissue culture plates at3000 per well and cultured at 37° C. for 18 hours. Test compounds weredissolved and diluted to 300× in DMSO then diluted 1:40 in DMEM. Cellswere incubated with test compounds for 72 hours followed by incubationwith tetrazolium compound(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt; MTS) and the electron coupling reagent, phenazinemethosulfate (PMS) for 4 hours. MTS was chemically reduced bydehydrogenase in cells into formazan. The ability of compounds toinhibit cell growth in this assay is correlated with the reduction ofdehydrogenase enzyme activity found in metabolically active cells. Themeasurement of the absorbance of the formazan was assessed using aVictor (Perkin Elmer) microplate reader at 492 nm. The calculated IC₅₀value is the concentration of the test compound that causes a 50%decrease in the absorbance. Percent inhibition by representativecompounds of the present invention in MDA-MB231 and DLD-1 cancer cellsis shown in Table 4.

TABLE 4 DLD-1, MTS, MDA-MB-231, MTS, Compound 72 hours (% 72 hours (% NoInhibition) inhibition) 5 96 98 8 99 94 15 98 83 21 58 69 22 98 99 39 9797 52 97 98 53 96 99 58 10 59 59 48 53 62 93 78 63 98 76 64 26 51 81 9899 82 97 92 86 97 98 90 89 81 93 98 99 115 98 99 117 97 99 136 97 76 15797 98 160 53 81

1. A compound having formula I:

or a pharmaceutically acceptable salt or ester thereof, wherein: R₁ isH, unsubstituted or substituted C₁-C₆ alkyl or Q₁-T₁; R₂ is H,unsubstituted or substituted C₁-C₆ alkyl or Q₂-T₂; or R₁ and R₂,together with the atom they attach to, form an unsubstituted orsubstituted heteroaryl or heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S; R₃ is H,unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆, C(O)R₅ orS(O)₂R₅; R₄ is H or unsubstituted or substituted C₁-C₆ alkyl; R₅ and R₆are each independently H, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substitutedheteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S; n is 0, 1 or 2; each R_(p) is independently OH, halogen, nitro,cyano or unsubstituted C₁-C₆ alkyl; Q₁ and Q₂ are each independently abond or unsubstituted or substituted C₁-C₆ alkyl linker; and T₁ and T₂are each independently unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.
 2. The compound of claim 1,wherein n is
 0. 3. The compound of claim 2, wherein R₃ and R₄ are eachH.
 4. The compound of claim 2, wherein R₃ is C(O)OR₅ and R₄ is H.
 5. Thecompound of claim 4, wherein R₅ is unsubstituted or substituted C₁-C₆alkyl.
 6. The compound of claim 2, having formula II:

or a pharmaceutically acceptable salt or ester thereof, wherein: R₂ isH, unsubstituted or substituted C₁-C₆ alkyl or Q₂-T₂; R₃ is H,unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆, C(O)R₅ orS(O)₂R₅; R₅ and R₆ are each independently H, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S; Q₁ and Q₂ are eachindependently a bond or unsubstituted or substituted C₁-C₆ alkyl linker;T₂ is unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S; m is 0, 1, 2, 3, 4 or 5; and each R_(q) is independently OH,halogen, nitro, cyano, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ alkoxy, unsubstituted or substitutedC₆-C₁₀ aryloxy, amino, unsubstituted or substituted C₁-C₆ alkylamino,unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted orsubstituted C₆-C₁₀ aryl, unsubstituted or substituted heteroarylcomprising one or two 5- or 6-member rings and 1-4 heteroatoms selectedfrom N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle orunsubstituted or substituted heterocycle comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S.
 7. Thecompound of claim 6, wherein R₃ is H.
 8. The compound of claim 6,wherein R₃ is C(O)OR₅.
 9. The compound of claim 8, wherein R₅ isunsubstituted or substituted C₁-C₆ alkyl.
 10. The compound of claim 6,wherein Q₁ is a bond, or a methyl, ethyl or a propyl linker.
 11. Thecompound of claim 6, wherein R₂ is H.
 12. The compound of claim 6,wherein R₂ is methyl, ethyl, propyl or butyl.
 13. The compound of claim6, wherein R₂ is Q₂-T₂.
 14. The compound of claim 6, wherein Q₂ is abond, or a methyl, ethyl or a propyl linker.
 15. The compound of claim2, having formula III:

or a pharmaceutically acceptable salt or ester thereof, wherein: R₃ isH, unsubstituted or substituted C₁-C₆ alkyl, C(O)OR₅, C(O)NR₅R₆, C(O)R₅or S(O)₂R₅; R₅ and R₆ are each independently H, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₆-C₁₀ aryl,unsubstituted or substituted heteroaryl comprising one or two 5- or6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S; o is 0, 1, 2, 3, 4 or 5; andeach R, is independently OH, halogen, nitro, cyano, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ alkoxy,unsubstituted or substituted C₆-C₁₀ aryloxy, amino, unsubstituted orsubstituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted orsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, unsubstituted or substitutedC₃-C₁₀ carbocycle or unsubstituted or substituted heterocycle comprisingone or two 5- or 6-member rings and 1-4 heteroatoms selected from N, Oand S; or any two adjacent R_(r), together with the carbon atoms theyattach to, form a 5- or 6-member ring which optionally comprises 1-4heteroatoms selected from N, O and S and optionally is substituted. 16.The compound of claim 15, wherein R₃ is H.
 17. The compound of claim 15,wherein R₃ is C(O)OR₅.
 18. The compound of claim 15, wherein R₅ isunsubstituted or substituted C₁-C₆ alkyl.
 19. The compound of claim 1,selected from:

or a pharmaceutically acceptable salt or ester thereof.
 20. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a salt, solvate, hydrate or prodrugthereof, and a pharmaceutically acceptable carrier or excipient.
 21. Amethod of treating a cell proliferative disorder by administering to asubject in need thereof, a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, prodrug,metabolite, analog or derivative thereof, in combination with apharmaceutically acceptable carrier, such that the disorder is treated.22. The method of claim 21, further comprising administering to thesubject in need thereof, a second anti-proliferative agent.